Ophthalmic compositions for treating ocular hypertension

ABSTRACT

This invention relates to potent potassium channel blocker compounds of Formula I or a formulation thereof for the treatment of glaucoma and other conditions which leads to elevated intraoccular pressure in the eye of a patient. This invention also relates to the use of such compounds to provide a neuroprotective effect to the eye of mammalian species, particularly humans.

This application claims the benefit under 35 U.S.C. 119(e) of U.S.Provisional Application No. 60/499,628 filed Sep. 2, 2003.

BACKGROUND OF THE INVENTION

Glaucoma is a degenerative disease of the eye wherein the intraocularpressure is too high to permit normal eye function. As a result, damagemay occur to the optic nerve head and result in irreversible loss ofvisual function. If untreated, glaucoma may eventually lead toblindness. Ocular hypertension, i.e., the condition of elevatedintraocular pressure without optic nerve head damage or characteristicglaucomatous visual field defects, is now believed by the majority ofophthalmologists to represent merely the earliest phase in the onset ofglaucoma.

There are several therapies for treating glaucoma and elevatedintraocular pressure, but the efficacy and the side effect profiles ofthese agents are not ideal. Recently potassium channel blockers werefound to reduce intraocular pressure in the eye and therefore provideyet one more approach to the treatment of ocular hypertension and thedegenerative ocular conditions related thereto. Blockage of potassiumchannels can diminish fluid secretion, and under some circumstances,increase smooth muscle contraction and would be expected to lower IOPand have neuroprotective effects in the eye. (see U.S. Pat. Nos.5,573,758 and 5,925,342; Moore, et al., Invest. Ophthalmol. Vis. Sci 38,1997; WO 89/10757, WO94/28900, and WO 96/33719).

SUMMARY OF THE INVENTION

This invention relates to the use of potent potassium channel blockersor a formulation thereof in the treatment of glaucoma and otherconditions that are related to elevated intraocular pressure in the eyeof a patient. This invention also relates to the use of such compoundsto provide a neuroprotective effect to the eye of mammalian species,particularly humans. More particularly this invention relates to thetreatment of glaucoma and/or ocular hypertension (elevated intraocularpressure) using novel benzofurans, benzothiophenes, and their azaderivatives having the structural formula I:

whereor a pharmaceutically acceptable salt, enantiomer, diastereomer ormixture thereof: wherein,

-   R represents hydrogen, or C₁₋₆ alkyl;-   X represents —(CHR₇)_(p)—, or —(CHR₇)_(p)CO—;-   Y represents —CO(CH₂)_(n)—, (CH₂)_(n), —CH(OR)—, OR₆, or SR₆;-   Z=O or S;-   M1, M2, and M3 are independently CH or N;-   Q represents CR^(y), N, or O, wherein R₂ is absent when Q is O;-   R^(y) represents H, C₁₋₆ alkyl, —(CH₂)_(n)C₃₋₈ cycloalkyl,    —(CH₂)_(n)C₃₋₁₀ heterocyclyl, —(CH₂)_(n)C₅₋₁₀ heteroaryl, or    —(CH₂)_(n)C₆₋₁₀ aryl;-   R_(w) represents H, C₁₋₆ alkyl, —C(O)C₁₋₆ alkyl, —C(O)OC₁₋₆ alkyl,    —SO₂N(R)₂, —SO₂C₁₋₆ alkyl, —SO₂C₆₋₁₀ aryl, NO₂, CN or —C(O)N(R)₂;-   R₂ represents hydrogen, C₁₋₁₀ alkyl, OH, C₂₋₆ alkenyl, C₁₋₆ alkylSR,    —(CH₂)_(n)O(CH₂)_(m)OR, —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₁₋₆ alkoxy,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₃₋₈ cycloalkyl,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₃₋₈cycloalkenyl,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₃₋₁₀ heterocyclyl, —N(R)₂, —COOR, or    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₆₋₁₀ aryl, said alkyl, cycloalkyl,    heterocyclyl, or aryl optionally substituted with 1-5 groups    selected from R^(a);-   R₃ represents hydrogen, C₁₋₁₀ alkyl, C₂₋₆ alkenyl,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₃₋₈ cycloalkyl,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)cycloalkenyl,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₃₋₁₀ heterocyclyl,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)COOR,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₆₋₁₀ aryl,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)NHR₈,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)N(R)₂,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)N(R)₃,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)N(R₈)₂,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)NHCOOR,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)N(R₈)CO₂R,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)N(R₈)COR,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)NHCOR,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)CONH(R₈), aryl,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₁₋₆ alkoxy, CF₃,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)SO₂R,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)SO₂N(R)₂,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)CON(R)₂,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)CONHC(R)₃,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)CONHC(R)₂CO₂R,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)COR₈, nitro, cyano or halogen, said    alkyl, cycloalkyl, alkoxy, heterocyclyl, or aryl optionally    substituted with 1-5 groups of R^(a);    or, when Q equals CR^(y) or N, R₂ and R₃ taken together with the    intervening CR^(y) or N form a 3-10 membered carbocyclic or    heterocyclic ring or fused ring optionally interrupted by 1-2 atoms    of O, S, C(O) or NR, and optionally having 1-5 double bonds, and    optionally substituted by 1-3 groups selected from R^(a);-   R₄ and R₅ independently represent hydrogen, C₁₋₆ alkoxy, OH, C₁₋₆    alkyl, C₁₋₆ alkyl-S, C₁₋₆ alkyl-CO—, C₁₋₆ alkenyl, C₃₋₈ cycloalkoxy,    C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-S, C₃₋₈ cycloalkyl-CO—, COOR, SO₃H,    —O(CH₂)_(n)N(R)₂, —O(CH₂)_(n)CO₂R, —OPO(OH)₂, CF₃, —N(R)₂, nitro,    cyano, C₁₋₆ alkylamino, or halogen;-   R₆ represents hydrogen, C₁₋₁₀ alkyl,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₆₋₁₀ aryl,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₅₋₁₀ heteroaryl, NR_(c)R_(d),    —NR—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₆₋₁₀ aryl,    —N—((CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₆₋₁₀ aryl)₂,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₃₋₁₀ heterocyclyl,    —NR—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₃₋₁₀ heterocyclyl,    —N—((CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₃₋₁₀ heterocyclyl)₂ (C₆₋₁₀ aryl)O—,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₃₋₈ cycloalkyl, —COOR, —C(O)CO₂R, said    aryl, cycloalkyl, heteroaryl, heterocyclyl and alkyl optionally    substituted with 1-3 groups selected from R^(a);-   R_(c) and R_(d) independently represent H, C1-6 alkyl, C₂₋₆ alkenyl,    —(CH₂)_(n)C₆₋₁₀ aryl, —(CH₂)_(n)C₅₋₁₀ heteroaryl, C₁₋₆ alkylSR,    —(CH₂)_(n)O(CH₂)_(m)OR, —(CH₂)_(n)C₁₋₆ alkoxy, or —(CH₂)_(n)C₃₋₈    cycloalkyl;    or R_(c) and R_(d) taken together with the intervening N atom form a    4-10 membered heterocyclic carbon ring optionally interrupted by 1-2    atoms of O, S, C(O) or NR, and optionally having 1-4 double bonds,    and optionally substituted by 1-3 groups selected from R^(a);-   R₇ represents hydrogen, C₁₋₆ alkyl, —(CH₂)_(n)COOR or    —(CH₂)_(n)N(R)₂,-   R₈ represents —(CH₂)_(n)C₃₋₈ cycloalkyl, —(CH₂)_(n 3-10)    heterocyclyl, C₁₋₆ alkoxy or —(CH₂)_(n)C₅₋₁₀ heteroaryl,    —(CH₂)_(n)C₆₋₁₀ aryl said cycloalkyl, heterocyclyl, aryl or    heteroaryl optionally substituted with 1-3 groups selected from    R^(a);-   R^(a) represents F, Cl, Br, I, CF₃, N(R)₂, NO₂, CN, —COR₈, —CONHR₈,    —CON(R₈)₂, —O(CH₂)_(n)COOR, —NH(CH₂)_(n)OR, —COOR, —OCF₃, —NHCOR,    —SO₂R, —SO₂NR₂, —SR, (C₁-C₆ alkyl)O—, —(CH₂)_(n)O(CH₂)_(m)OR,    —(CH₂)_(n)C₁₋₆ alkoxy, (aryl)O—, —OH, (C₁-C₆ alkyl)S(O)_(m)—,    H₂N—C(NH)—, (C₁-C₆ alkyl)C(O)—, (C₁-C₆ alkyl)OC(O)NH—, —(C₁-C₆    alkyl)NR_(w)(CH₂)_(n)C₃₋₁₀ heterocyclyl-R_(w), —(C₁-C₆    alkyl)O(CH₂)_(n)C₃₋₁₀ heterocyclyl-R_(w), —(C₁-C₆    alkyl)S(CH₂)_(n)C₃₋₁₀ heterocyclyl-R_(w), —(C₁-C₆ alkyl)—C₃₋₁₀    heterocyclyl-R_(w), —(CH₂)_(n)—Z¹—C(═Z²)N(R)₂, —(C₂₋₆    alkenyl)NR_(w)(CH₂)_(n)C₃₋₁₀ heterocyclyl-R_(w), —(C₂₋₆    alkenyl)O(CH₂)_(n)C₃₋₁₀ heterocyclyl-R_(w), —(C₂₋₆    alkenyl)S(CH₂)_(n)C₃₋₁₀ heterocyclyl-R_(w), —C₂₋₆ alkenyl)-C₃₋₁₀    heterocyclyl-R_(w), —(C₂₋₆ alkenyl)-Z¹—C(═Z²)N(R)₂, —(CH₂)_(n)SO₂R,    —(CH₂)_(n)SO₃H, —(CH₂)_(n)PO(OR)₂, —(CH₂)_(n)OH,    —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)OPO(OR)₂, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl,    C₃₋₁₀ heterocyclyl, C₂₋₆ alkenyl, and C₁-C₁₀ alkyl, said alkyl,    alkenyl, alkoxy, heterocyclyl and aryl optionally substituted with    1-3 groups selected from C₁-C₆ alkyl, CN, NO₂, —(CH₂)_(n)OH,    —(CH₂)_(n)OPO(OR)₂, CON(R)₂ and COOR;-   Z¹ and Z² independently represents NR_(w), O, CH₂, or S;-   m is 0-3;-   n is 0-3;-   p is 0-3 and-   q is 0-1.

This and other aspects of the invention will be realized upon inspectionof the invention as a whole.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to novel potassium channel blockers ofFormula I. It also relates to a method for decreasing elevatedintraocular pressure or treating glaucoma by administration, preferablytopical or intra-camaral administration, of a composition containing apotassium channel blocker of Formula I described hereinabove and apharmaceutically acceptable carrier. Use of a compound of formula I inclaim 1 for the manufacture of a medicament for the treatment of ocularhypertension or glaucoma.

One embodiment of this invention is realized when Y is —CO(CH₂)_(n) andall other variables are as originally described. A subembodiment of thisinvention is realized when n is 0.

One embodiment of this invention is realized when Q is —N— and all othervariables are as originally described. A subembodiment of this inventionis realized when R₂ is C₁₋₁₀ alkyl and R₃ is C₁₋₁₀ alkyl and said alkyloptionally substituted with 1 to 3 groups of R^(a).

Another embodiment is realized when Q equals CR^(y) or N, and R₂ and R₃taken together with the intervening CR^(y) or N form a 3-10 memberedcarbocyclic or heterocyclic ring or fused ring optionally interrupted by1-2 atoms of O, S, C(O) or NR, and optionally having 1-5 double bonds,and optionally substituted by 1-3 groups selected from R^(a);

Another embodiment of this invention is realized when Y is CH(OR) andall other variables are as originally described.

In another embodiment R_(w) is selected from H, C₁₋₆ alkyl, —C(O)C₁₋₆alkyl and —C(O)N(R)₂ and all other variables are as originallydescribed.

In another embodiment X is —(CHR₇)_(p)—, p is 1-3 and all othervariables are as originally described.

In another embodiment X is —(CHR₇)_(p)CO—, p is 1-3 and all othervariables are as originally described.

In another embodiment Z is S and all other variables are as originallydescribed.

In another embodiment Z is O and all other variables are as originallydescribed.

In another embodiment one of R₄ and R₅ is H and the other is C₁₋₆alkoxy, halo or hydrogen.

Another embodiment of this invention is realized when M1, M2, and M3 areCH and all other variables are as originally described.

Another embodiment of this invention is realized when at least one ofM1, M2, and M3 is N and the other(s) is CH and all other variables areas originally described.

Still another embodiment of this invention is realized when R₆ is C₁₋₆alkyl, (CH₂)_(n)C₆₋₁₀ aryl, (CH₂)_(n)C₃₋₁₀ heterocyclyl, NR_(c)R_(d) or(CH₂)_(n)C₃₋₈ cycloalkyl, said alkyl, aryl, heterocyclyl and cycloalkyloptionally substituted with 1 to 5 groups of R^(a), and all othervariables are as originally described.

Yet another embodiment of this invention is realized when R₆ is(CH₂)_(n)C₆₋₁₀ aryl, NR_(c)R_(d), or (CH₂)_(n)C₃₋₁₀ heterocyclyl, saidaryl, and heterocyclyl optionally substituted with 1 to 5 groups ofR^(a), and all other variables are as originally described.

Yet another embodiment of this invention is realized when R₇ is hydrogenor C₁₋₆ alkyl, and all other variables are as originally described.

Still another embodiment of this invention is realized when Y is—CO(CH₂)_(n), Q is —N—, R₂ is C₁₋₁₀ alkyl or C₁₋₆ alkylOH and R₃ isC₁₋₁₀ alkyl and said alkyl optionally substituted with 1 to 5 groups ofR^(a). A sub-embodiment of this invention is realized when n is 0 and Zis O. Another sub-embodiment of this invention is realized when n is 0and Z is S.

Still another embodiment of this invention is realized when Y is—CO(CH₂)_(n), Q is CR^(y), R₂ is C₁₋₁₀ alkyl or C₁₋₆alkylOH and R₃ isC₁₋₁₀ alkyl and said alkyl optionally substituted with 1 to 5 groups ofR^(a). A sub-embodiment of this invention is realized when n is 0 and Zis O. Another sub-embodiment of this invention is realized when n is 0and Z is S.

Still another embodiment of this invention is realized when Y is—CO(CH₂)_(n), Q is O, R₂ is absent and R₃ is C₁₋₁₀ alkyl and said alkyloptionally substituted with 1 to 5 groups of R^(a). A subembodiment ofthis invention is realized when n is 0.

Still another embodiment of this invention is realized when Q is —N—, Yis —CO(CH₂)_(n), n=0, Z is S, and R₆ is C₁₋₆ alkyl, (CH₂)_(n)C₆₋₁₀ aryl,(CH₂)_(n)C₅₋₁₀ heteroaryl, (CH₂)_(n)C₃₋₁₀ heterocyclyl, NR_(c)R_(d) or(CH₂)_(n)C₃₋₈ cycloalcyl, said alkyl, aryl, heteroaryl, heterocyclyl andalkyl optionally substituted with 1 to 3 groups of R^(a). Asub-embodiment of this invention is realized when M1, M2 and M3 are CH,X is —(CHR₇)_(p)CO—, p is 1-3, R₂ is C₁₋₁₀ alkyl or C₁₋₆ alkylOH and R₃is (CH₂)_(n)C₃₋₁₀ heterocyclyl, said heterocyclyl and alkyl optionallysubstituted with 1 to 3 groups of R^(a).

Still another embodiment of this invention is realized when Q is —CRy—,n=0, Z is S, and R₆ is C₁₋₆ alkyl, (CH₂)_(n)C₆₋₁₀ aryl, (CH₂)_(n)C₅₋₁₀heteroaryl, (CH₂)_(n)C₃₋₁₀ heterocyclyl, NR_(c)R_(d) or (CH₂)_(n)C₃₋₈cycloalkyl, said alkyl, aryl, heteroaryl, heterocyclyl and alkyloptionally substituted with 1 to 3 groups of R^(a).

Still another embodiment of this invention is realized when Q is —N—, Yis —CO(CH₂)_(n), n=0, Z is O, and R₆ is C₁₋₆ alkyl, (CH₂)_(n)C₆₋₁₀ aryl,(CH₂)_(n)C₅₋₁₀ heteroaryl, (CH₂)_(n)C₃₋₁₀ heterocyclyl, NR_(c)R_(d) or(CH₂)_(n)C₃₋₈ cycloalkyl, said alkyl, aryl, heteroaryl, heterocyclyl andalkyl optionally substituted with 1 to 3 groups of R^(a). Asub-embodiment of this invention is realized when M1, M2 and M3 are CH,X is —(CHR₇)_(p)CO—, p is 1-3, R₂ is C₁₋₁₀ alkyl or C₁₋₆ alkylOH and R₃is (CH₂)_(n)C₃₋₁₀ heterocyclyl, said heterocyclyl and alkyl optionallysubstituted with 1 to 3 groups of R^(a).

Still another embodiment of this invention is realized when Q is —CRy-,n=0, Z is O, and R₆ is C₁₋₆ alkyl, (CH₂)_(n)C₆₋₁₀ aryl, (CH₂)_(n)C₅₋₁₀heteroaryl, (CH₂)_(n)C₃₋₁₀ heterocyclyl, NR_(c)R_(d) or (CH₂)_(n)C₃₋₈cycloalkyl, said alkyl, aryl, heteroaryl, heterocyclyl and alkyloptionally substituted with 1 to 3 groups of R^(a).

Another embodiment of this invention is realized when there is a freehydroxyl group in the compound of formula I. A subembodiment of thisinvention is realized when the hydroxyl group is derivatized to give aphosphate group: —OPO(OH)₂.

Another embodiment of the instant invention is realized when R^(a) isselected from F, Cl, Br, I, CF₃, N(R)₂, NO₂, CN, —CONHR₈, —CON(R₈)₂,—O(CH₂)_(n)COOR, —NH(CH₂)_(n)OR, —COOR, —OCF₃, —NHCOR, —SO₂R, —SO₂NR₂,—SR, (C₁-C₆ alkyl)O—, —(CH₂)_(n)O(CH₂)_(m)OR, —(CH₂)_(n)C₁₋₆ alkoxy,(aryl)O—, —OH, (C₁-C₆ alkyl)S(O)_(m)—, H₂N—C(NH)—, (C₁-C₆ alkyl)C(O)—,(C₁-C₆ alkyl)OC(O)NH—, (CH₂)_(n)C₃₋₁₀ heterocyclyl, —(C₁-C₆alkyl)NR_(w)(CH₂)_(n)C₃₋₁₀ heterocyclyl-R_(w),—(CH₂)_(n)-Z¹—C(═Z²)N(R)₂, —(C₂₋₆ alkenyl)NR_(w)(CH₂)_(n)C₃₋₁₀heterocyclyl-R_(w),—(C₂₋₆ alkenyl)-Z¹—C(═Z²)N(R)₂, —(CH₂)_(n)SO₂R,—(CH₂)_(n)SO₃H, —(CH₂)_(n)OPO(OR)₂, C₂₋₆ alkenyl, and C₁-C₁₀ alkyl, saidalkyl, heterocyclyl and alkenyl, optionally substituted with 1-3 groupsselected from C₁-C₆ alkyl, and COOR;

Examples of compounds to be used in this invention are as follows:

-   N,N-Bibutyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetamide,-   2-[2(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N,N-diisobutylacetamide,-   N-(Cyclopropylmethyl)-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-propylacetamide,-   N-Cyclohexyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethylacetamide,-   2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N,N-propylacetamide,-   N-Butyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethylacetamide,-   2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N,N-bis(3-methylbutyl)acetamide,-   2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethyl-N-(3-methylbutyl)acetamide,-   N-Butyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-propylacetamide,-   1-{5-Methoxy-3-[2-(trans-octahydroisoquinolin-2(1H)-yl)-2-oxoethyl]-1-benzofuran-2-yl}-2,2-dimethylpropan-1-one,-   1-{5-Methoxy-3-[2-(cis-octahydroisoquinolin-2(1H)-yl)-2-oxoethyl]-1-benzofuran-2-yl}-2,2-dimethylpropan-1-one,-   1-(3-{2-[Trans-2,5-dipropylpyrrolidin-1-yl]-2-oxoethyl}-5-methoxy-1-benzofuran-2-yl)-2,2-dimethylpropan-1-one,-   1-(3-{2-[Cis-2,5-dipropylpyrrolidin-1-yl]-2-oxoethyl}-5-methoxy-1-benzofuran-2-yl)-2,2-dimethylpropan-1-one,-   N-(3,3-Dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetamide,-   N-(3,3-Dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethylacetamide,-   1-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-3,3-dimethylbutan-2-one,-   2-(2-Benzoyl-5-methoxy-1-benzofuran-3-yl)-N,N-dibutylacetamide,-   1-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-3,3-dimethylpentan-2-one-   2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N,N-di-n-butylacetamide;-   2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N,N-diisobutylacetamide;-   N-(cyclopropylmethyl)-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N-propylacetamide;-   N-cyclohexyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N-ethylacetamide;-   2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N,N-dipropylacetamide;-   N-butyl-2-[2-(2,2-ethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N-ethylacetamide;-   2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N-ethyl-N-(3-methylbutyl)acetamide;-   N-butyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N-propylacetamide;-   2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N,N-bis(3-methylbutyl)acetamide;-   1-{5-methoxy-3-[2-(trans-octahydroisoquinolin-2(1H)-yl)-2-oxoethyl]-1-benzothien-2-yl}-2,2-dimethylpropan-1-one;-   1-{5-methoxy-3-[2-(cis-octahydroisoquinolin-2(1H)-yl)-2-oxoethyl]-1-benzothien-2-yl}-2,2-dimethylpropan-1-one;-   1-(3-{2-[(trans-2,5-dipropylpyrrolidin-1-yl]-2-oxoethyl}-5-methoxy-1-benzothien-2-yl)-2,2-dimethylpropan-1-one;-   1-(3-{2-[(cis-2,5-dipropylpyrrolidin-1-yl]-2-oxoethyl}-5-methoxy-1-benzothien-2-yl)-2,2-dimethylpropan-1-one;-   N-(3,3-dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N-ethylacetamide;-   1-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-3,3-dimethylbutan-2-one;-   N-Butyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofaran-3-yl]-N-methylacetamide;-   2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-methyl-N-(3-methylbutyl)acetamide;-   2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N,N-di-n-butylacetamide;-   2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N,N-diisobutylacetamide;-   N-(cyclopropylmethyl)-2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N-propylacetamide;-   N-cyclohexyl-2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N-ethylacetamide;-   2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N,N-dipropylacetamide;-   N-butyl-2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N-ethylacetamide;-   2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N-ethyl-N-3-methylbutyl)acetamide;-   N-butyl-2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N-propylacetamide;-   2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N,N-bis(3-methylbutyl)acetamide;-   1-{5-fluoro-3-[2-(trans-octahydroisoquinolin-2(1H)-yl)-2-oxoethyl]-1-benzothien-2-yl}-2,2-dimethylpropan-1-one;-   1-{5-fluoro-3-[2-(cis-octahydroisoquinolin-2(1H)-yl)-2-oxoethyl]-1-benzothien-2-yl}-2,2-dimethylpropan-1-one;-   1-(3-{2-[(trans-2,5-dipropylpyrrolidin-1-yl]-2-oxoethyl}-5-fluoro-1-benzothien-2-yl)-2,2-dimethylpropan-1-one;-   1-(3-{2-[(cis-2,5-dipropylpyrrolidin-1-yl]-2-oxoethyl}-5-fluoro-1-benzothien-2-yl)-2,2-dimethylpropan-1-one;-   N-(3,3-dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N-ethylacetamide;-   2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N,N-di-n-butylacetamide;-   2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N,N-diisobutylacetamide;-   N-(cyclopropylmethyl)-2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N-propylacetamide;-   N-cyclohexyl-2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N-ethylacetamide;-   2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N,N-dipropylacetamide;-   N-butyl-2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N-ethylacetamide;-   2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N-ethyl-N-(3-methylbutyl)acetamide;-   N-butyl-2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N-propylacetamide;-   2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N,N-bis(3-methylbutyl)acetamide;-   1-{3-[2-(trans-octahydroisoquinolin-2(1H)-yl)-2-oxoethyl]-1-benzothien-2-yl}-2,2-dimethylpropan-1-one;-   1-{3-[2-(cis-octahydroisoquinolin-2(1H)-yl)-2-oxoethyl]-1-benzothien-2-yl}-2,2-dimethylpropan-1-one;-   1-(3-{2-[(trans-2,5-dipropylpyrrolidin-1-yl]-2-oxoethyl}-1-benzothien-2-yl)-2,2-dimethylpropan-1-one;-   1-(3-{2-[(cis-2,5-dipropylpyrrolidin-1-yl]-2-oxoethyl}-1-benzothien-2-yl)-2,2-dimethylpropan-1-one;-   N-(3,3-dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N-ethylacetamide;    or a pharmaceutically acceptable salt, enantiomer, diastereomer or    mixture thereof.

The invention is described herein in detail using the terms definedbelow unless otherwise specified.

The compounds of the present invention may have asymmetric centers,chiral axes and chiral planes, and occur as racemates, racemic mixtures,and as individual diastereomers, with all possible isomers, includingoptical isomers, being included in the present invention. (See E. L.Eliel and S. H. Wilen Stereochemistry of Carbon Compounds (John Wileyand Sons, New York 1994), in particular pages 1119-1190)

When any variable (e.g. aryl, heterocycle, R¹, R⁶ etc.) occurs more thanone time in any constituent, its definition on each occurrence isindependent at every other occurrence. Also, combinations ofsubstituents/or variables are permissible only if such combinationsresult in stable compounds.

The term “alkyl” refers to a monovalent alkane (hydrocarbon) derivedradical containing from 1 to 10 carbon atoms unless otherwise defined.It may be straight, branched or cyclic. Preferred alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopropylcyclopentyl and cyclohexyl. When the alkyl group is said to besubstituted with an alkyl group, this is used interchangeably with“branched alkyl group”.

Cycloalkyl is a cyclic specie of alkyl containing from 3 to 15 carbonatoms, unless otherwise defined, without alternating or resonatingdouble bonds between carbon atoms. It may contain from 1 to 4 rings,which are fused. Examples of such cycloalkyl elements include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

Alkenyl is C₂-C₆ alkenyl.

Alkoxy refers to an alkyl group of indicated number of carbon atomsattached through an oxygen bridge, with the alkyl group optionallysubstituted as described herein. Said groups are those groups of thedesignated length in either a straight or branched configuration and iftwo or more carbon atoms in length, they may include a double or atriple bond. Exemplary of such alkoxy groups are methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy,isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like.

Halogen (halo) refers to chlorine, fluorine, iodine or bromine.

Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and thelike, as well as rings which are fused, e.g., naphthyl, phenanthrenyland the like. An aryl group thus contains at least one ring having atleast 6 atoms, with up to five such rings being present, containing upto 22 atoms therein, with alternating (resonating) double bonds betweenadjacent carbon atoms or suitable heteroatoms. Examples of aryl groupsare phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl,phenanthryl, anthryl or acenaphthyl and phenanthrenyl, preferablyphenyl, naphthyl or phenanthrenyl. Aryl groups may likewise besubstituted as defined. Preferred substituted aryls include phenyl andnaphthyl.

The term heterocyclyl or heterocyclic, as used herein, represents astable 3- to 7-membered monocyclic or stable 8- to 11-membered bicyclicheterocyclic ring which is either saturated or unsaturated, and whichconsists of carbon atoms and from one to four heteroatoms selected fromthe group consisting of N, O, and S, and including any bicyclic group inwhich any of the above-defmed heterocyclic rings is fused to a benzenering. The heterocyclic ring may be attached at any heteroatom or carbonatom which results in the creation of a stable structure. A fusedheterocyclic ring system may include carbocyclic rings and need includeonly one heterocyclic ring. The term heterocycle or heterocyclicincludes heteroaryl moieties. Examples of such heterocyclic elementsinclude, but are not limited to, azepinyl, benzimidazolyl,benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl,benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,dihydropyrrolyl, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl,imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl,isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl,morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl,piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl,quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.Preferably, heterocycle is selected from 2-azepinonyl, benzimidazolyl,2-diazapinonyl, dihydroimidazolyl, dihydropyrrolyl, imidazolyl,2-imidazolidinonyl, indolyl, isoquinolinyl, morpholinyl, piperidyl,piperazinyl, pyridyl, pyrrolidinyl, 2-piperidinonyl, 2-pyrimidinonyl,2-pyrollidinonyl, quinolinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,and thienyl.

The term “heteroatom” means O, S or N, selected on an independent basis.

The term “heteroaryl” refers to a monocyclic aromatic hydrocarbon grouphaving 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10atoms, containing at least one heteroatom, O, S or N, in which a carbonor nitrogen atom is the point of attachment, and in which one or twoadditional carbon atoms is optionally replaced by a heteroatom selectedfrom O or S, and in which from 1 to 3 additional carbon atoms areoptionally replaced by nitrogen heteroatoms, said heteroaryl group beingoptionally substituted as described herein. Examples of suchheterocyclic elements include, but are not limited to, benzimidazolyl,benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl,benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl,imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl,isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl,pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl,quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,thiazolyl, thienofuryl, thienothienyl, thienyl and triazolyl. Additionalnitrogen atoms may be present together with the first nitrogen andoxygen or sulfur, giving, e.g., thiadiazole.

This invention is also concerned with compositions and methods oftreating ocular hypertension or glaucoma by administering to a patientin need thereof one of the compounds of formula I alone or incombination with one or more of the following active ingredients, incombination with a β-adrenergic blocking agent such as timolol,betaxolol, levobetaxolol, carteolol, levobunolol, a parasympathomimeticagent such as epinephrine, iopidine, brimonidine, clonidine,para-aminoclonidine, carbonic anhydrase inhibitor such as dorzolamide,acetazolamide, metazolamide or brinzolamide, an EP4 agonist (such asthose disclosed in WO 02/24647, WO 02/42268, EP 1114816, WO 01/46140,PCT Appln. No. CA2004000471, and WO 01/72268), a prostaglandin such aslatanoprost, travaprost, unoprostone, rescula, S1033 (compounds setforth in U.S. Pat. Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151,444);a hypotensive lipid such as lumigan and the compounds set forth in U.S.Pat. No. 5,352,708; a neuroprotectant disclosed in U.S. Pat. No.4,690,931, particularly eliprodil and R-eliprodil as set forth in WO94/13275, including memantine; an agonist of 5-HT2 receptors as setforth in PCT/US00/31247, particularly1-(2-aminopropyl)-3-methyl-1H-imdazol-6-ol fumarate and2-(3-chloro-6-methoxy-indazol-1-yl)-1-methyl-ethylamine or a mixturethereof. An example of a hypotensive lipid (the carboxylic acid group onthe α-chain link of the basic prostaglandin structure is replaced withelectrochemically neutral substituents) is that in which the carboxylicacid group is replaced with a C₁₋₆ alkoxy group such as OCH₃ (PGF_(2a)1-OCH₃), or a hydroxy group (PGF_(2a) 1-OH).

Preferred potassium channel blockers are calcium activated potassiumchannel blockers. More preferred potassium channel blockers are highconductance, calcium activated potassium (Maxi-K) channel blockers.Maxi-K channels are a family of ion channels that are prevalent inneuronal, smooth muscle and epithelial tissues and which are gated bymembrane potential and intracellular Ca²⁺.

The present invention is based upon the finding that maxi-K channels, ifblocked, inhibit aqueous humor production by inhibiting net solute andH₂O efflux and therefore lower IOP. This finding suggests that maxi-Kchannel blockers are useful for treating other ophthamologicaldysfunctions such as macular edema and macular degeneration. It is knownthat lowering IOP promotes blood flow to the retina and optic nerve.Accordingly, the compounds of this invention are useful for treatingmacular edema and/or macular degeneration. Use of a compound of formulaI in claim 1 for the manufacture of a medicament for the treatment ofmacular edema and/or macular degeneration It is believed that maxi-Kchannel blockers which lower IOP are useful for providing aneuroprotective effect. They are also believed to be effective forincreasing retinal and optic nerve head blood velocity and increasingretinal and optic nerve oxygen by lowering IOP, which when coupledtogether benefits optic nerve health. As a result, this inventionfurther relates to a method for increasing retinal and optic nerve headblood velocity, increasing retinal and optic nerve oxygen tension aswell as providing a neuroprotective effect or a combination thereof. Useof a compound of formula I in claim 1 for the manufacture of amedicament for increasing retinal and optic nerve head blood velocity,retinal and optic nerve oxygen tension and providing a neuroprotectiveeffect.

A number of marketed drugs function as potassium channel antagonists.The most important of these include the compounds Glyburide, Glipizideand Tolbutamide. These potassium channel antagonists are useful asantidiabetic agents. The compounds of this invention may be combinedwith one or more of these compounds to treat diabetes. Use of a compoundof formula I in claim 1 for the manufacture of a medicament for thetreatment of diabetes.

Potassium channel antagonists are also utilized as Class 3antiarrhythmic agents and to treat acute infarctions in humans. A numberof naturally occuring toxins are known to block potassium channelsincluding Apamin, Iberiotoxin, Charybdotoxin, Noxiustoxin, Kaliotoxin,Dendrotoxin(s), mast cell degranuating (MCD) peptide, and β-Bungarotoxin(β-BTX). The compounds of this invention may be combined with one ormore of these compounds to treat arrhythmias. Use of a compound offormula I in claim 1 in combination with these compounds for themanufacture of a medicament for the treatment of arrhythmias

Depression is related to a decrease in neurotransmitter release. Currenttreatments of depression include blockers of neurotransmitter uptake,and inhibitors of enzymes involved in neurotransmitter degradation whichact to prolong the lifetime of neurotransmitters.

Alzheimer's disease is also characterized by a diminishedneurotransmitter release. Three classes of drugs are being investigatedfor the treatment of Alzheimer's disease cholinergic potentiators suchas the anticholinesterase drugs (e.g., physostigmine (eserine), andTacrine (tetrahydroaminocridine)); nootropics that affect neuronmetabolism with little effect elsewhere (e.g., Piracetam, Oxiracetam;and those drugs that affect brain vasculature such as a mixture ofergoloid mesylates amd calcium channel blocking drugs includingNimodipine. Selegiline, a monoamine oxidase B inhibitor which increasesbrain dopamine and norepinephrine has reportedly caused mild improvementin some Alzheimer's patients. Aluminum chelating agents have been ofinterest to those who believe Alzheimer's disease is due to aluminumtoxicity. Drugs that affect behavior, including neuroleptics, andanxiolytics have been employed. Anxiolytics, which are mildtranquilizers, are less effective than neuroleptics The presentinvention is related to novel compounds which are useful as potassiumchannel antagonists. Use of a compound of formula I in claim 1 for themanufacture of a medicament for the treatment of depression andAlzheimer's disease.

The compounds of this invention may be combined with anticholinesterasedrugs such as physostigmine (eserine) and Tacrine(tetrahydroaminocridine), nootropics such as Piracetam, Oxiracetam,ergoloid mesylates, selective calcium channel blockers such asNimodipine, or monoamine oxidase B inhibitors such as Selegiline, in thetreatment of Alzheimer's disease. The compounds of this invention mayalso be combined with Apamin, Iberiotoxin, Charybdotoxin, Noxiustoxin,Kaliotoxin, Dendrotoxin(s), mast cell degranuating (MCD) peptide,β-Bungarotoxin (β-BTX) or a combination thereof in treating arrhythmias.The compounds of this invention may further be combined with Glyburide,Glipizide, Tolbutamide or a combination thereof to treat diabetes.

The herein examples illustrate but do not limit the claimed invention.Each of the claimed compounds are potassium channel antagonists and arethus useful in the described neurological disorders in which it isdesirable to maintain the cell in a depolarized state to achieve maximalneurotransmitter release. The compounds produced in the presentinvention are readily combined with suitable and known pharmaceuticallyacceptable excipients to produce compositions which may be administeredto mammals, including humans, to achieve effective potassium channelblockage.

For use in medicine, the salts of the compounds of formula I will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention or oftheir pharmaceutically acceptable salts. When the compound of thepresent invention is acidic, suitable “pharmaceutically acceptablesalts” refers to salts prepared form pharmaceutically acceptablenon-toxic bases including inorganic bases and organic bases. Saltsderived from inorganic bases include aluminum, ammonium, calcium,copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc and the like. Particularly preferred are theammonium, calcium, magnesium, potassium and sodium salts. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as arginine, betaine caffeine, choline,N,N¹-dibenzylethylenediamine, diethylamin, 2-dimethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine tripropylamine, tromethamineand the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and thelike. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric and tartaric acids.

The preparation of the pharmaceutically acceptable salts described aboveand other typical pharmaceutically acceptable salts is more fullydescribed by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977:66:1-19.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specific amounts, aswell as any product which results, directly or indirectly, fromcombination of the specific ingredients in the specified amounts.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, sex and response of the individual patient, as well as theseverity of the patient's symptoms.

The maxi-K channel blockers used can be administered in atherapeutically effective amount intravaneously, subcutaneously,topically, transdermally, parenterally or any other method known tothose skilled in the art.

Ophthalmic pharmaceutical compositions are preferably adapted fortopical administration to the eye in the form of solutions, suspensions,ointments, creams or as a solid insert. Ophthalmic formulations of thiscompound may contain from 0.01 ppm to 1% and especially 0.1 ppm to 1% ofmedicament. Higher dosages as, for example, about 10% or lower dosagescan be employed provided the dose is effective in reducing intraocularpressure, treating glaucoma, increasing blood flow velocity or oxygentension. For a single dose, from between 0.1 ng to 5000 ug, preferably 1ng to 500 ug, and especially 10 ng to 100 ug of the compound can beapplied to the human eye.

The pharmaceutical preparation which contains the compound may beconveniently admixed with a non-toxic pharmaceutical organic carrier, orwith a non-toxic pharmaceutical inorganic carrier. Typical ofpharmaceutically acceptable carriers are, for example, water, mixturesof water and water-miscible solvents such as lower alkanols oraralkanols, vegetable oils, polyalkylene glycols, petroleum based jelly,ethyl cellulose, ethyl oleate, carboxymethyl-cellulose,polyvinylpyrrolidone, isopropyl myristate and other conventionallyemployed acceptable carriers. The pharmaceutical preparation may alsocontain non-toxic auxiliary substances such as emulsifying, preserving,wetting agents, bodying agents and the like, as for example,polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500,4,000, 6,000 and 10,000, antibacterial components such as quaternaryammonium compounds, phenylmercuric salts known to have cold sterilizingproperties and which are non-injurious in use, thimerosal, methyl andpropyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredientssuch as sodium borate, sodium acetates, gluconate buffers, and otherconventional ingredients such as sorbitan monolaurate, triethanolamine,oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodiumsulfosuccinate, monothioglycerol, thiosorbitol, ethylenediaminetetracetic acid, and the like. Additionally, suitable ophthalmicvehicles can be used as carrier media for the present purpose includingconventional phosphate buffer vehicle systems, isotonic boric acidvehicles, isotonic sodium chloride vehicles, isotonic sodium boratevehicles and the like. The pharmaceutical preparation may also be in theform of a microparticle formulation. The pharmaceutical preparation mayalso be in the form of a solid insert. For example, one may use a solidwater soluble polymer as the carrier for the medicament. The polymerused to form the insert may be any water soluble non-toxic polymer, forexample, cellulose derivatives such as methylcellulose, sodiumcarboxymethyl cellulose, (hydroxyloweralkyl cellulose), hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose;acrylates such as polyacrylic acid salts, ethylacrylates,polyactylamides; natural products such as gelatin, alginates, pectins,tragacanth, karaya, chondrus, agar, acacia; the starch derivatives suchas starch acetate, hydroxymethyl starch ethers, hydroxypropyl starch, aswell as other synthetic derivatives such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, neutralizedcarbopol and xanthan gum, gellan gum, and mixtures of said polymer.

Suitable subjects for the administration of the formulation of thepresent invention include primates, man and other animals, particularlyman and domesticated animals such as cats and dogs.

The pharmaceutical preparation may contain non-toxic auxiliarysubstances such as antibacterial components which are non-injurious inuse, for example, thimerosal, benzalkonium chloride, methyl and propylparaben, benzyldodecinium bromide, benzyl alcohol, or phenylethanol;buffering ingredients such as sodium chloride, sodium borate, sodiumacetate, sodium citrate, or gluconate buffers; and other conventionalingredients such as sorbitan monolaurate, triethanolamine,polyoxyethylene sorbitan monopalmitylate, ethylenediamine tetraaceticacid, and the like.

The ophthalmic solution or suspension may be administered as often asnecessary to maintain an acceptable IOP level in the eye. It iscontemplated that administration to the mamalian eye will be about onceor twice daily.

For topical ocular administration the novel formulations of thisinvention may take the form of solutions, gels, ointments, suspensionsor solid inserts, formulated so that a unit dosage comprises atherapeutically effective amount of the active component or somemultiple thereof in the case of a combination therapy.

The following examples, given by way of illustration, are demonstrativeof the present invention.

Definitions of the Terms Used in the Examples are as Follows:

-   SM—Starting material,-   DMSO—dimethyl sulfoxide,-   TLC—thin layer chromatography,-   SGC—silica gel chromatography,-   h=hr=hour,-   TBF—tetrahydrofuran,-   DMF—dimethylformamide,-   LDA—lithium diisopropylamide,-   HOBt—1-hydroxybenzotriazole hydrate-   EDC—1(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   NMR—nuclear magnetic resonance,-   TFA—trifluoroacetic acid,-   DIEA—N,N-diisopropylethylamine-   min—minute,-   LC/MS—liquid chromatography/mass spectrometry,-   HPLC—high performance liquid chromatography,-   equiv=eq=equivalent,    General Experimental Conditions: NMR spectra were recorded at room    temperature on Varian Instruments referenced to residual solvent    peak. LC-MS were measured on an Aglient HPLC and Micromass ZQ    detector with electrospray ionization using a 2.0×50 mm X-Terra C18    column and 10˜98% MeCN gradient over 3.75 minutes followed by 98%    MeCN for 1 minute. The aqueous and MeCN eluents contained 0.06 and    0.05% (v/v) trifluoroacetic acid, respectively. Mass peaks are    listed in decreasing order of relative abundance. Preparative HPLC    separations were done using a C18 column such as YMC 20×150 mm 5 μ    ProC18 column or a 9.4×250 mm SB-C18 Zorbax column.

The compounds of this invention can be made, with modification whereappropriate, in accordance with Schemes 1-8.

Scheme 1 illustrates a method for preparing one of two commonintermediates, benzofuran 4. When the commercially availablehydroxyacetophenone 1 was treated with stoichiometric amounts of1-bromopinacolone and cesium carbonate at room temperature, analysisindicated that the only product was the ether 2 (Method A). When aslight excess of cesium carbonate was employed in the reaction, theproduct was a mixture of two diastereomers of 3 plus benzofuran 4(Method B). The intermediate 3 can be converted to 4 in high yields withcatalytic amount of cesium carbonate at slightly elevated temperature.This two-step conversion of 1 to 4 can be simplified by conducting thereaction at elevated temperature with a slight excess of cesiumcarbonate (Method C).

Scheme 2 illustrates the preparation of a second common intermediate,acid 5. The benzofuran 4 can be carboxylated by treatment with a strongbase such as LDA followed by carbon dioxide to give acid 5.

Some compounds of the present invention can be prepared as illustratedin Scheme 3. Many coupling conditions could give amides 6 as the finalproduct. It is usually accompanied by side-product 7. Heating theside-product with amine can give the desired amide also. Thisside-product can be produced by omitting the dialkyl amine during thecoupling reaction. Therefore, the sequence 5-7-6 is an alternative routefor the preparation of the compounds of this invention.

The preparation of another type of compounds of this invention isillustrated in Scheme 4. Quenching the homo-enolate from 4 withtrimethyl acetaldehyde gave a mixture of two hydroxyketones 8 and 9.Their oxidation affords diketone 10 as illustrated by the conversion of8 to 10.

Similarly, substituted analogues such as 11 can be transformed to 13 and14 using analogous methods. Higher homologues of 1 could be reacted inthe same fashion to give desired products 18 and 19 when R7 is nothydrogen (Scheme 6).

Scheme 7 shows the preparation of amides in the benzothiophene class.The starting 2-mercaptobenzoic acid is either commercially available orprepared based a literature method (C. F. H. Allen and D. D. MacKay Org.Syn. Coll Vol II, 580). Treatment of 2-mercaptobenzoic acid with excessmethyl lithium provided the methyl ketone (Topolshi, J. Org. Chem. 1995,60, 5585). This was cyclized with α-bromoketone to give benzothiophenein one step using a new procedure. Carboxylation gives the acetic acidderivative and the subsequence conversion to amides are uneventful.

Scheme 8 illustrates the synthesis of ketones in the benzothiopheneclass. A homoaldol reaction between the 3-methyl benzothiophene fromScheme 7 and an aldehyde provided the alcohol precursor to the ketoneand an isomeric alcohol. The alcohol intermediate was oxidized to givethe ketone using the Swern oxidation.

EXAMPLE 1

N,N-Bibutyl-2-[2-(2,2-ethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetamideStep A:1-(5-Methoxy-3-methyl-1-benzofuran-2-yl)-2,2-dimethylpropan-1-one

DMF (4 mL) was added to a mixture of 166 mg1-(2-hydroxy-5-methoxyphenyl)ethanone and 370 mg cesium carbonatefollowed by 188 mg 1-bromopinacolone. After heating this mixture in an85° C. oil bath for 3 hours, it was poured into cold water and extractedwith ether. The combined ether extract was washed with water, 1.5 NNaOH, water, and saturated brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure to give a crude product. It waspurified on silica gel (9:1 hexanes and EtOAc) to give the titlecompound as a colorless solid. ¹H NMR (CDCl₃, 500 MHz) δ 7.41 (d, J=9.0Hz, 1H), 7.11 (dd, J=2.5 & 9.0 Hz, 1H), 7.04 (d, J=2.5 Hz, 1H), 3.90 (s,3H), 2.59 (s, 3H), 1.43 (s, 9H).

Step B: [2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]aceticacid

To a solution of 1.23 g1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-2,2-dimethylpropan-1-oneprepared as described in Step A above in 50 mL anhydrous THF at −78° C.was added 5.0 mL 2.0 M LDA in a mixture of heptane, THF, andethylbenzene. After stirring for 15 minutes, carbon dioxide gas wasbubbled into the reaction mixture for 5 minutes. The cooling bath wasremoved and the reaction mixture was allowed to warm up to roomtemperature. It was concentrated under reduced pressure to removesolvents. The residue was diluted with ether and extracted with 0.1 MNaOH (3×). The combine aqueous extract was washed with ether, acidifiedwith concentrated HCl to pH ˜1, and extracted with ether. The combinedether extract was washed with saturated brine, dried over anhydrousNa₂SO₄, and evaporated to give title compound as colorless solid. ¹H NMR(CDCl₃, 500 MHz) δ 7.47 (d, 9.0 Hz, 1H), 7.18 (dd, 2.5 & 9.2 Hz, 1H),7.12 (d, 2.5 Hz, 1H), 4.05 (s, 2H), 3.91 (s, 3H), 1.46 (s, 9H). LC-MS:3.54 min. (m/Z=245.1, 273.1, 291).

Step C:N,N-Bibutyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetamide

Dissolve a mixture of 17 mg[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid fromthe Step B above and 18.5 mg HOBt in 1 mL dry DMF. Add 14.9 μLdi-n-butylamine followed by 23.0 mg EDC and 35 μL DIEA. This solutionwas heated at 40° C. for 2 hours. It was purified directly on RP-HPLCusing 65-100% MeCN gradient. The fractions containing pure product werepooled and lyophilized to give the title compound. LC-MS: 4.46 min.(m/Z=318.2, 402.2, 424.2).

EXAMPLE 2

2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N,N-diisobutylacetamide

Dissolve a mixture of 17 mg[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid fromthe Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 15.4 μLdi-i-butylamine followed by 23.0 mg EDC and 35 μL DIEA. This solutionwas heated at 40° C. for 2 hours. It was purified directly on RP-HPLCusing 65-100% MeCN gradient. The fractions containing pure product werepooled and lyophilized to give the title compound. LC-MS: 4.42 min.(m/Z=318.2, 402.2, 424.2).

EXAMPLE 3

N-(Cyclopropylmethyl)-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-propylacetamide

Dissolve a mixture of 17 mg[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid fromthe Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 12.6 μLN-propylcyclopropanemethylamine followed by 23.0 mg EDC and 35 μL DIEA.This solution was heated at 40° C. for 2 hours. It was purified directlyon RP-HPLC using 60-100% MeCN gradient. The fractions containing pureproduct were pooled and lyophilized to give the title compound. LC-MS:4.17 min. (m/Z=386.2, 302.1, 408.1).

EXAMPLE 4

N-Cyclohexyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethylacetamide

Dissolve a mixture of 17 mg[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid fromthe Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 13.2 μLN-ethylcyclohexylamine followed by 23.0 mg EDC and 35 μL DIEA. Thissolution was heated at 40° C. for 2 hours. It was purified directly onRP-HPLC using 65-100% MeCN gradient. The fractions containing pureproduct were pooled and lyophilized to give the title compound. LC-MS:4.34 min. (m/Z=400.2, 422.1, 316.1).

EXAMPLE 5

2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N,N-dipropylacetamide

Dissolve a mixture of 17 mg[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid fromthe Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 12.1 μLdipropylamine followed by 23.0 mg EDC and 35 μL DIEA. This solution washeated at 40° C. for 2 hours. It was purified directly on RP-HPLC using60-100% MeCN gradient. The fractions containing pure product were pooledand lyophilized to give the title compound. LC-MS: 4.16 min. (m/Z=290.1,374.2, 396.1).

EXAMPLE 6

N-Butyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethylacetamide

Dissolve a mixture of 17 mg[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid fromthe Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 12.0 μLN-ethylbutylamine followed by 23.0 mg EDC and 35 μL DIEA. This solutionwas heated at 40° C. for 2 hours. It was purified directly on RP-HPLCusing 60-100% MeCN gradient. The fractions containing pure product werepooled and lyophilized to give the title compound. LC-MS: 4.15 min.(m/Z=290.1, 374.2, 396.1).

EXAMPLE 7

2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N,N-bis(3-methylbutyl)acetamide

Dissolve a mixture of 17 mg[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid fromthe Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 18.0 μLdi-iso-amylamine followed by 23.0 mg EDC and 35 μL DIEA. This solutionwas heated at 40° C. for 2 hours. It was purified directly on RP-HPLCusing 70-100% MeCN gradient. The fractions containing pure product werepooled and lyophilized to give the title compound. LC-MS: 4.67 min.(m/Z=430.4, 346.2, 452.2).

EXAMPLE 8

2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethyl-N-(3-methylbutyl)acetamide

Dissolve a mixture of 17 mg[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid fromthe Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 10.1 mgN-ethyl-iso-amylamine followed by 23.0 mg EDC and 35 μL DIEA. Thissolution was heated at 40° C. for 2 hours. It was purified directly onRP-HPLC using 65-100% MeCN gradient. The fractions containing pureproduct were pooled and lyophilized to give the title compound. LC-MS:4.29 min. (m/Z=304.2, 388.2, 410.2).

EXAMPLE 9

N-Butyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-propylacetamide

Dissolve a mixture of 17 mg[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid fromthe Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 13.6 μLN-propylbutylamine followed by 23.0 mg EDC and 35 μL DIEA. This solutionwas heated at 40° C. for 2 hours. It was purified directly on RP-HPLCusing 65-100% MeCN gradient. The fractions containing pure product werepooled and lyophilized to give the title compound. LC-MS: 4.31 min.(m/Z=304.2, 388.2, 410.2).

EXAMPLE 10

1-{5-Methoxy-3-[2-(trans-octahydroisoquinolin-2(1H)-yl)-2-oxoethyl]-1-benzofuran-2yl}-2,2-dimethylpropan-1-one

Dissolve a mixture of 17 mg[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid fromthe Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 12.3 mgtrans-decahydroisoquinoline followed by 23.0 mg EDC and 35 μL DIEA. Thissolution was heated at 40° C. for 2 hours. It was purified directly onRP-HPLC using 65-100% MeCN gradient. The fractions containing pureproduct were pooled and lyophilized to give the title compound. LC-MS:4.34 min. (m/Z=412.3, 328.2, 434.2).

EXAMPLE 11

1-{5-Methoxy-3-[2-(cis-octahydroisoquinolin-2(1H)-yl)-2-oxoethyl]-1-benzofuran-2-yl}-2,2-dimethylpropan-1-one

Dissolve a mixture of 17 mg[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid fromthe Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 12.3 mgcis-decahydroisoquinoline followed by 23.0 mg EDC and 35 μL DIEA. Thissolution was heated at 40° C. for 2 hours. It was purified directly onRP-HPLC using 65-100% MeCN gradient. The fractions containing pureproduct were pooled and lyophilized to give the title compound. LC-MS:4.41 min. (m/Z=412.3, 328.2, 434.2).

EXAMPLE 12

1-(3-{2-[Trans-2,5-dipropylpyrrolidin-1-yl]-2-oxoethyl}-5-methoxy-1-benzofuran-2-yl)-2,2-dimethylpropan-1-oneStep A: N,N′-Dimethoxy-N,N′-dimethylsuccinamide

Dissolve 136.2 g of succinyl dichloride and 180.0 gN,O-dimethylhydroxylamine hydrochloride in 1.2 L dichloromethane andcool it in an ice bath. Add 305.9 g pyridine from an addition funnelwith stir over 1.5 hours. Let the reaction mixture warm up to roomtemperature over night. Pour the reaction mixture into ice and water andseparate the layers. Wash the organic layer with cold 2 N HCl (2×),water, 5% NaHCO₃ (2×), and saturated brine. Dry over anhydrous Na₂SO₄and evaporate to give crude product. It was washed with 3:1 hexanes anddichloromethane and dried to give the title compound as a light tansolid. ¹H NMR (CDCl₃, 500 MHz) δ: 3.70 (s, 6H), 3.15 (s, 6H), 2.74 (s,4H).

Step B: Decane-4,7-dione

Cool a suspension of 20.42 g N,N′-dimethoxy-N,N′-dimethylsuccinamidefrom the Step A above in 1 L anhydrous ether in an ice bath undernitrogen. Add 300 mL of 2 M propylmagnesium chloride in ether over 15minutes with mechanical stir. Continue to stir the reaction mixture inthe cooling bath for 2.25 hours. Quench the reaction by adding 30 mLethanol in 50 mL ether over 30 minutes. Pour the resulting suspensioninto 1 L ice and water containing 75 mL concentrated HCl. Separate thelayers, wash the organic layer with dilute HCl, 5% NaHCO₃ and saturatedbrine. Dry over anhydrous Na₂SO₄. Evaporate the clear yellowish solutionto give the title compound as yellow solid. ¹H NMR (CDCl₃, 500 MHz)

: 2.69 (s, 4H), 2.46 (t, J=7.4 Hz, 4H), 1.60˜1.67 (m, 4H), 0.935 (t,J=7.5 Hz, 6H).

Step C: Cis- and trans-1-benzyl-2,5-dipropylpyrrolidine

Dissolve 11.92 g decane-4,7-dione from the Step B above in 4.62 g aceticacid and 100 mL methanol. Add 1.16 g potassium hydroxide pellets. Stirto dissolve the potassium hydroxide. Cool the reaction mixture in an iceacetone bath at −15° C. Add 7.50 g benzylamine followed immediately with5.4 g sodium cyanoborohydride in several portions. Let the reactionmixture warm up to room temperature over two days. Add 45 mL 4 N HCldrop-wise and stir for 30 minutes. Evaporate the reaction mixture underreduced pressure to remove most of the solvents. Dilute the residue withwater, filter off some white solid, and extract the aqueous layer withether. This ether solution contained 2,5-dipropylpyrrole. Cool theaqueous layer with an ice bath and add solid sodium hydroxide in smallportions with stir until pH ˜13. Dissolve the white solid above in thismixture. Extract with ether several times. Wash the combined ethersolution with saturated brine, dry over anhydrous Na₂SO₄ and evaporateto give the crude 1-benzyl-2,5-dipropylpyrrolidine. The cis and transisomers were separated on silica gel (5˜10% EtOAc in hexanes with 1%Et₃N). The fast eluting isomer wastrans-1-benzyl-2,5-dipropylpyrrolidine. ¹H NMR (CDCl₃, 500 MHz) δ 7.38(d, J=7.6 Hz, 2H), 7.29˜7.33 (m, 2H), 7.21˜7.24 (m, 1H), 3.83 (d, J=13.9Hz, 1H), 3.66 (d, J=14.0 Hz, 1H), 2.86 (br s, 2H), 1.85˜1.94 (m, 2H),1.45˜1.60 (m, 4H), 1.27˜1.37 (m, 2H), 1.09˜1.20 (m, 4H), 0.875 (t, J=7.2Hz, 6H). The slower-eluting isomer wascis-1-benzyl-2,5-dipropylpyrrolidine. ¹H NMR (CDCl₃, 500 MHz)

7.29˜7.35 (m, 4H), 7.24˜7.26 (m, 1H), 3.77 (s, 2H), 2.53˜2.58 (m, 2H),1.77˜1.84 (m, 2H), 1.52˜1.58 (m, 2H), 1.27˜1.44 (m, 4H), 1.13˜1.25 (m,4H), 0.865 (t, J=7.2 Hz, 6H).

Step D: Trans-2,5-dipropylpyrrolidine

Dissolve 1.56 g trans-1-benzyl-2,5-dipropylpyrrolidine from the Step Cabove in 100 mL methanol and add 4.01 g ammonium formate and 156 mgPd(OH)₂/C. Let the reaction mixture stir under nitrogen over night.Filter the reaction mixture through Celite to remove the catalyst.Concentrate the filtrate under reduced pressure to give a white solidresidue. Suspend it in a small amount of water, add 5 mL 5 N NaOHsolution, extract with ether several times, wash the combined ethersolution with saturated brine, dry over anhydrous Na₂SO₄, and evaporateto give the title compound as yellow liquid. ¹H NMR (CDCl₃, 500 MHz)

3.11˜3.16 (m, 2H), 1.91˜1.98 (m, 2H), 1.26˜1.50 (m, 10H), 0.93 (t, J=7.1Hz, 6H). LC-MS: 1.89 min. (M+H=156.1).

Step E:1-(3-{2-[Trans-2,5-dipropylpyrrolidin-1-yl]-2-oxoethyl}-5-methoxy-1-benzofuran-2-yl)-2,2-dimethylpropan-1-one

Dissolve a mixture of 17 mg[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid fromthe Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 13.7 mgtrans-2,5-dipropylpyrrolidine from the Step D above followed by 23.0 mgEDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. Itwas purified directly on RP-HPLC using 70-100% MeCN gradient. Thefractions containing pure product were pooled and lyophilized to givethe title compound. LC-MS: 4.58 min. (m/Z 428.3, 344.2, 450.3).

EXAMPLE 13

1-(3-{2-[Cis-2,5-diproplpyrrolidin-1-yl]-2-oxoethyl}-5-methoxy-1-benzofuran-2-yl)-2,2-dimethylpropan-1-oneStep A: Cis-2,5-dipropylpyrrolidine

The title compound was prepared in the same manner fromcis-1-benzyl-2,5-dipropylpyrrolidine from Step C Example 12 using theprocedure in Step D Example 12. ¹H NMR (CDCl₃, 500 MHz)

2.94˜3.00 (m, 2H), 1.81˜1.89 (m, 2H), 1.25˜1.54 (m, 10H), 0.94 (t, J=7.2Hz, 6H). LC-MS: 1.83 min. (M+H=156.1).

Step B:1-(3-{2-[Cis-2,5-dipropylpyrrolidin-1-yl]-2-oxoethyl}-5-methoxy-1-benzofuran-2-yl)-2,2-dimethylpropan-1-one

Dissolve a mixture of 17 mg[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid fromthe Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 13.7 mgcis-2,5-dipropylpyrrolidine from the Step A above followed by 23.0 mgEDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. Itwas purified directly on RP-HPLC using 70-100% MeCN gradient. Thefractions containing pure product were pooled and lyophilized to givethe title compound. LC-MS: 4.59 min. (m/Z=428.3, 344.2, 450.3).

EXAMPLE 14

N-(3,3-Dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetamide

To a mixture of 29 mg[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid fromthe Step B Example 1, 23 mg HOBt, and 38.3 mg EDC was added 1 mL dryDMF. Add 24.9 mg (3,3-dimethylbutyl)amine hydrochloride followed by 61μL DIEA. This solution was heated at 45° C. for 2 hours. It was purifieddirectly on RP-HPLC using 60-75% MeCN gradient. The fractions containingpure product were pooled and lyophilized to give the title compound.LC-MS: 4.08 min. (m/Z=290.1, 374.2, 396.2).

EXAMPLE 15

N-(3,3-Dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethylacetamideStep A: N-Ethyl-3,3-dimethylbutan-1-amine hydrochloride

The title compound was prepared from commercially available ethylamineand 3,3-dimethylbutyraldehye using sodium triacetoxyborohydride(Abdel-Magid, et al. J. Org. Chem. 1996, 61, 3849). ¹H NMR (CD₃OD, 500MHz) δ 3.07 (q, 7.1 Hz, 2H), 2.97˜3.02 (m, 2H), 1.57˜1.62 (m, 2H), 1.32(t, 7.2 Hz, 3H), 0.98 (s, 9H).

Step B: 1-tert-butyl-6-methoxy-3H-pyrano[3,4-b][1]benzofuran-3-one

Dissolve 98 mg[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid fromthe Step B Example 1, 176 μL DIEA, and 114 mg HOBt in 3.5 mL dry DMF.Add 97.1 mg EDC and let the mixture stir at room temperature over night.It was purified directly on RP-HPLC using 50-70% MeCN gradient. Thefractions containing pure product were pooled and lyophilized to givethe title compound as yellow solid. ¹H NMR (CDCl₃, 500 MHz)

7.34 (dd, J=1.3 & 8.4 Hz, 1H), 7.25˜7.29 (m, 2H), 6.54 (s, 1H), 3.92 (s,3H), 1.52 (s, 9H). LC-MS: 3.55 min. (M+H=273.1).

Step C:N-(3,3-dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethylacetamide

To a mixture containing 21.8 mg1-tert-butyl-6-methoxy-3H-pyrano[3,4-b][1]benzofuran-3-one from the StepB above and 21.6 mg N-Ethyl-3,3-dimethylbutan-1-amine hydrochloride fromthe Step A above in 0.75 mL DMF was 26 μL DIEA. The mixture was heatedin 45° C. oil bath over night. It was purified directly on RP-HPLC using65˜85% MeCN gradient. The fractions containing pure product were pooledand lyophilized to give the title compound. LC-MS: 4.38 min. (m/Z=318.2,402.3, 424.3). Alternative preparation ofN-(3,3-dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethylacetamide

To a mixture of 7.7 mg[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid fromthe Step B Example 1, 6.1 mg HOBt, and 10.2 mg EDC was added 0.5 mL dryDMF. Add 6.6 N-ethyl-3,3-dimethylbutan-1-amine hydrochloride from theStep A above followed by 16 μL DIEA. This solution was heated at 45° C.over night. It was purified directly on RP-HPLC using 65-80% MeCNgradient. The fractions containing pure product were pooled andlyophilized to give the title compound. LC-MS: 4.38 min. (m/Z=424.3,318.2, 402.3).

EXAMPLE 16

1-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-3,3-dimethylbutan-2-oneStep A:1-[3-(2-Hydroxy-3,3-dimethylbutyl)-5-methoxy-1-benzofuran-2-yl]-2,2-dimethylpropan-1-one

To a solution of 0.23 g1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-2,2-dimethylpropan-1-one fromStep A Example 1 in 10 mL anhydrous THF at −78° C. under nitrogen wasadded 0.93 mL 2 M LDA in heptane, THF, and ethylbenzene. After 15minutes, 0.160 g trimethylacetaldehyde was added. Remove the coolingbath and let the reaction mixture warm up to room temperature. After 30minutes, evaporate the reaction mixture under reduced pressure to removesolvents. Dilute the residue with ether, wash with 1 M HCl (2×) andsaturated brine, dry over anhydrous Na₂SO₄, and evaporate to give acrude product. It was purified on RP-HPLC using 75˜100% MeCN in waterwithout TFA to give the title compound as colorless solid afterlyophilization. ¹H NMR (CDCl₃, 500 MHz)

7.44 (d, J=9.2 Hz, 1H), 7.12 (dd, J=2.7 & 9.1 Hz, 1H), 7.02 (d, J=2.5Hz, 1H), 3.89 (s, 3H), 3.48˜3.52 (br m, 1H), 3.40 (br d, J=7.0 Hz, 1OH),3.10˜3.16 (m, 2H), 1.43 (s, 9H), 1.10 (s, 9H). LC-MS: 4.23 min.(m/Z=245.2, 315.2, 355.2=M+Na, 259.1). A faster-eluting isomericside-product was also isolated during purification:1-[2-(1-hydroxy-2,2-dimethylpropyl)-5-methoxy-1-benzofuran-3-yl]-3,3-dimethylbutan-2-one.¹H NMR (CDCl₃, 500 MHz)

7.34 (d, J=8.9 Hz, 1H), 6.87 (dd, J=2.5 & 9.0 Hz, 1H), 6.79 (d, J=2.5Hz, 1H), 4.53 (s, 1H), 3.99 (d, J=17.6 Hz, 1H), 3.92 (d, J=17.4 Hz, 1H),3.84 (s, 3H), 1.32 (s, 9H), 1.06 (s, 9H). LC-MS: 3.77 min.(m/Z=355.2=M+Na, 315.2). The structures of the isomers were furtherconfirmed by COSY and NOESY spectroscopy.

Step B:1-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-3,3-dimethylbutan-2-one

Cool 1.5 mL dichloromethane in dry ice bath under nitrogen. Add 38 mgoxalyl chloride followed by 47 mg DMSO. Stir for 30 minutes. Add asolution of 49.9 mg1-[3-(2-hydroxy-3,3-dimethylbutyl)-5-methoxy-1-benzofuran-2-yl]-2,2-dimethylpropan-1-onefrom the Step A above in 2.5 mL dichloromethane. After another 25minutes, 167 μL triethylamine were added. After stirring for additional25 minutes, the reaction mixture was removed from the cooling bath andallowed to warm to room temperature. After 2 hours, solvents wereremoved under reduced pressure and the residue was purified directly onRP-HPLC using 70-100% MeCN gradient. The fractions containing pureproduct were pooled and lyophilized to give the title compound. ¹H NMR(CDCl₃, 500 MHz)

7.43 (d, J=8.9 Hz, 1H), 7.10 (dd, J=2.5 & 8.9 Hz, 1H), 6.90 (d, J=2.6Hz, 1H), 4.39 (s, 2H), 3.87 (s, 3H), 1.42 (s, 9H), 1.34 (s, 9H). LC-MS:4.17 min. (m/Z=247.2, 353.3, 331.4).

EXAMPLE 17

2-(2-Benzoyl-5-methoxy-1-benzofuran-3-yl)-N,N-dibutylacetamide Step A:(5-Methoxy-3-methyl-1-benzofuran-2-yl)(phenyl)methanone

The title compound was prepared from1-2-hydroxy-5-methoxyphenyl)ethanone, 2-bromoacetophenone, and cesiumcarbonate using the procedure described in Step A, Example 1. ¹H NMR(CDCl₃, 500 MHz) δ 8.03˜8.07 (m, 2H), 7.55˜7.59 (m, 1H), 7.47˜7.51 (m,2H), 7.40 (d, J=9.0 Hz, 1H), 7.08 (dd, J=2.6 & 9.0 Hz, 1H), 7.03 (d,J=2.5 Hz, 1H), 3.86 (s, 3H), 2.59 (s, 3H). LC-MS: 3.83 min. (M+H=267.2)

Step B: (2-Benzoyl-5-methoxy-1-benzofuran-3-yl)acetic acid

The title compound was prepared from(5-methoxy-3-methyl-1-benzofuran-2-yl)(phenyl)methanone from the Step Aabove using procedure in Step B Example 1. The crude acidic fraction wasfurther purified on RP-HPLC using 40˜75% MeCN gradient. The fractionscontaining pure product were pooled and lyophilized to give the titlecompound. ¹H NMR (CDCl₃, 500 MHz) δ 8.22˜8.24 (m, 2H), 7.69˜7.73 (m,1H), 7.58˜7.62 (m, 2H), 7.51 (d, J=8.9 Hz, 1H), 7.21 (dd, J=2.5 & 8.9Hz, 1H), 7.18 (d, J=2.3 Hz, 1H), 4.17 (s, 2H), 3.93 (s, 3H). LC-MS: 3.26min. (m/Z=265.2, 293.2).

Step C: 2-(2-Benzoyl-5-methoxy-1-benzofuran-3-yl)-N,N-dibutylacetamide

To a mixture of 10.6 mg (2-benzoyl-5-methoxy-1-benzofuran-3-yl)aceticacid from the Step B above, 7.8 mg HOBt and 13.1 mg EDC were added 6.6mg dibutylamine and 0.5 mL DMF followed by 21 μL DIEA. After stirring atroom temperature over night, it was heated in a 55° C. oil bath for 8hours. It was purified directly on RP-HPLC using 60-95% MeCN gradient.The fractions containing pure product were pooled and lyophilized togive the title compound. ¹H NMR (CDCl₃, 500 MHz)

8.10˜8.13 (m, 2H), 7.62˜7.66 (m, 1H), 7.53˜7.57 (m, 2H), 7.45 (d, J=8.9Hz, 1H), 7.275 (d, J=2.7 Hz, 1H), 7.14 (dd, J=2.7 & 9.1 Hz, 1H), 4.39(s, 2H), 3.89 (s, 3H), 3.43˜3.47 (m, 2H), 3.37˜3.40 (m, 2H), 1.51˜1.61(m, 4H), 1.26˜1.38 (m, 4H), 0.94 (t, J=7.3 Hz, 3H), 0.90 (t, J=7.3 Hz,3H). LC-MS: 4.24 min. (m/Z=422.3, 444.3).

EXAMPLE 18

1-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-3,3-dimethylpentan-2-oneStep A:1-[3-(2-Hydroxy-3,3-dimethylpentyl)-5-methoxy-1-benzofuran-2-yl]-2,2-dimethylpropan-1-one

To a solution of 0.493 g1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-2,2-dimethylpropan-1-one fromStep A Example 1 in 20 mL anhydrous THF at −78° C. under nitrogen wasadded 2.0 mL 2 M LDA in heptane, THF, and ethylbenzene. After 50minutes, 0.40 g 2,2-dimethylbutanal was added. Remove the cooling bathand let the reaction mixture warm up to room temperature. After 70minutes, the reaction was quenched by adding 2 mL saturated ammoniumchloride and the reaction mixture was evaporated under reduced pressureto remove solvents. Dilute the residue with ether, wash with 1 M HCl(2×) and saturated brine, dry over anhydrous Na₂SO₄, and evaporate togive a crude product. It was purified on RP-HPLC using 65˜100% MeCN inwater without TFA to give the title compound as colorless solid afterlyophilization. ¹H NMR (CDCl₃, 500 MHz)

7.44 (d, 9.1 Hz, 1H), 7.20 (d, 2.0 Hz, 1H), 7.10 (dd, 2.5 & 9.1 Hz, 1H),3.86 (s, 3H), 3.58 (dd, 1.6 & 10.6 Hz, 1H), 3.29˜3.34 (m, 1H), 2.90˜2.95(m, 1H), 1.51˜1.59 (m, 1H), 1.39˜1.46 (m, 1H), 1.40 (s, 9H), 1.02 (s,3H), 1.01 (s, 3H), 0.92 (t, 7.6 Hz, 3H). LC-MS: 4.47 min. (m/Z=329.3,369.2, 347). A faster-eluting isomeric side-product was also isolatedduring purification and was identified as1-[2-(1-hydroxy-2,2-dimethylpropyl)-5-methoxy-1-benzofuran-3-yl]-3,3-dimethylpentan-2-one.¹H NMR (CDCl₃, 500 MHz)

7.30 (d, 9.0 Hz, 1H), 6.84 (dd, 2.5 & 8.9 Hz, 1H), 6.75 (d, 2.5 Hz, 1H),4.44 (s, 1H), 4.07 (AB d, 18.5 Hz, 1H), 4.04 (AB d, 18.5 Hz, 1H), 3.78(s, 3H). 1.74 (q, 7.6 Hz, 2H), 1.263 (s, 3H), 1.260 (s, 3H), 0.99 (s,9H), 0.91 (t, 7.4 Hz, 3H). LC-MS: 3.95 min. (m/Z=369.3=M+Na, 329.3,).

Step B:1-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofaran-3yl]-3,3-dimethylpentan-2-one

The title compounds was prepared from1-[3-(2-hydroxy-3,3-dimethylpentyl)-5-methoxy-1-benzofuran-2-yl]-2,2-dimethylpropan-1-onefrom Step A above using procedure similar to that in Step B of Example16. LC-MS: 4.36 min. (m/Z=261.2, 367.3, 345.3).

EXAMPLE 19

N,N-Dibutyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]acetamideStep A: 1-(2-Mercapto-5-methoxyphenyl)ethanone

The title compound was prepared from crude 2-mercapto-5-methoxybenzoicacid from the method of Allen and MacKay (Org. Syn. Coll Vol II, 580)using the method by Topolsiki (J. Org. Chem. 1995, 60, 5585). It wasused without purification in the next step. LC-MS: 2.91 min. (m/Z=183).

Step B: 1-5-Methoxy-3-methyl-1-benzothien-2-yl)-2,2-dimethylpropan-1-one

The title compound was prepared from1-(2-mercapto-5-methoxyphenyl)ethanone from the Step A above using themethod similar to that in Step A Example 1. It was purified byrecrystallization from ethyl acetate. ¹H NMR (CDCl₃, 500 MHz)

7.70 (d, 8.7 Hz, 1H), 7.24 (d, 2.3 Hz, 1H), 7.135 (dd, 2.5 & 8.9 Hz,1H), 3.93 (s, 3H), 2.56 (s, 3H), 1.41 (s, 9H). LC-MS: 4.17 min.(m/Z=221.1, 179.0, 263.1).

Step C: [2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]aceticacid

The title compound was prepared from1-(5-methoxy-3-methyl-1-benzothien-2-yl)-2,2-dimethylpropan-1-one fromStep B above using the method described in Step B Example 1. ¹H NMR(CDCl₃, 500 MHz)

7.73 (d, 8.9 Hz, 1H), 7.46 (d, 2.3 Hz, 1H), 7.21 (dd, 2.6 & 9.0 Hz, 1H),4.01 (s, 2H), 3.95 (s, 3H), 1.47 (s, 9H). LC-MS: 3.48 min. (m/Z=261.1,289.1, 329.1, 307).

Step D: 1-tert-Butyl-6-methoxy-3H-[1]benzothieno[2,3-c]pyran-3-one

A round bottom flask was charged with 0.460 g[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]acetic acid fromthe Step C above, 0.345 g HOBt hydrate, and 0.504 g EDC HCl salt. Thismixture was dissolved in 15 mL anhydrous DMF and 0.582 g DIEA was added.The mixture turned bright yellow. After standing at room temperatureovernight, the mixture was poured into water and extracted with etherseveral times. The combined ether extract was washed with water (4×), 5%NaHCO₃, and saturated brine, dried over anhydrous Na₂SO₄, and evaporatedto give the title compound as a bright yellow solid. ¹H NMR (CDCl₃, 500MHz)

7.49 (d, 8.7 Hz, 1H), 7.35 (d, 2.5 Hz, 1H), 7.20 (dd, 2.5 & 8.9 Hz, 1H),6.65 (s, 1H), 3.92 (s, 3H), 1.51 (s, 9H). LC-MS: 3.77 min. (m/Z=289.3).

Step E:N,N-Dibutyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]acetamide

A solution of 21.6 mg of1-tert-butyl-6-methoxy-3H-[1]benzothieno[2,3-c]pyran-3-one from the StepD above and 29.1 mg di-n-butyl amine in 0.75 mL anhydrous DMF was heatedat 70° C. for six hours. The reaction mixture was purified on RP-HPLCusing 70˜100% MeCN gradient with 0.1% TFA. The product fractions werepooled and lyophilized to give the title compound as a white solid.LC-MS: 4.53 min. (m/Z=418.3, 440.2).

EXAMPLES 20˜32

Examples 20˜32 in Table 1 were prepared from1-tert-butyl-6-methoxy-3H-[1]benzothieno[2,3-c]pyran-3-one from the StepD of Example 19 and either three equivalents of an appropriate amine ortwo equivalents of an appropriate amine plus two equivalents of DIEAunder the conditions described in Step E of Example 19. In Example 32,an amine HCl salt was used with the doubled amount of DIEA. Thepreparation of amines for Examples 30˜32 were described in US2003/034959filed Nov. 4, 2003, incorporated herein by reference in its entirety.

TABLE 1 Examples 20~32

LC-MS Example R₁ R₂ t_(r), min. m/Z 20 i-Bu i-Bu 4.53 418.3, 440.2 21cyclopropylmethyl n-Pr 4.25 402.3, 424.2 22 cyclohexyl Et 4.43 416.3,438 23 n-Pr n-Pr 4.24 390.3, 412.2 24 n-Bu Et 4.24 390.3, 412.2 25i-Amyl Et 4.38 404.3, 426 26 n-Bu n-Pr 4.39 404.3, 426.2 27 i-Amyli-Amyl 4.76 446.2, 468.3 28

4.49 428.3, 450.2 29

4.45 428.4, 450.2 30

4.66 444.4, 466.3 31

4.69 444.4, 466.2 32 3,3-Dimethylbutyl Et 4.48 418.3, 440

EXAMPLE 33

1-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-3,3-dimethylbutan-2-oneStep A.1-[3-(2-Hydroxy-3,3-dimethylbutyl)-5-methoxy-1-benzothien-2-yl]-2,2-dimethylpropan-1-one

The title compound was prepared from1-(5-methoxy-3-methyl-1-benzothien-2-yl)-2,2-dimethylpropan-1-one (StepB, Example 19) using the procedure descried in Step A, Example 18. Theproducts were isolated using RP-HPLC employing a 65˜100% MeCN gradientwithout TFA. The title compound was isolated as the major product as awhite solid after lyophilization. ¹H NMR (CD₃OD, 500 MHz)

7.65 (d, 8.7 Hz, 1H), 7.12 (d, 2.3 Hz, 1H), 6.94 (dd, 2.5 & 8.7 Hz, 1H),4.62 (dd, 2.3 & 2.5 Hz, 1H), 3.87 (s, 3H), 3.00 (dd, 3.0 & 16.0 Hz, 1H),2.985 (dd, 2.0 & 16.0 Hz, 1H), 1.14 (s, 9H), 1.12 (s, 9H). LC-MS: 4.54min. (m/Z=331.2). A faster-eluting isomer was also isolated. It asidentified as1-[2-(1-hydroxy-2,2-dimethylpropyl)-5-methoxy-1-benzothien-3-yl]-3,3-dimethylbutan-2-one.Its ¹H NMR (CD₃OD, 500 MHz)

7.65 (d, 8.7 Hz, 1H), 6.94 (dd, 2.5 & 8.7 Hz, 1H), 6.83 (d, 2.5 Hz, 1H),4.68 (s, 1H), 4.27 (d, 18.8 Hz, 1H), 4.16 (d, 18.8 Hz, 1H), 3.79 (s,3H), 1.33 (s, 9H), 1.01 (s, 9H). LC-MS: 3.91 min. (m/Z=371.1). Unlikethe cases in Examples 16 and 18, the two isomers in the current Exampleappeared to interconvert under ambient temperature and neutral pHspontaneously.

Step B.1-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-3,3-dimethylbutan-2-one

The title compound was prepared from1-[3-(2-hydroxy-3,3-dimethylbutyl)-5-methoxy-1-benzothien-2-yl]-2,2-dimethylpropan-1-onefrom the Step A above using the procedure in Step B, Example 18. It wasisolated as a white solid following RP-HPLC purification (70˜100% MeCN)and lyophilization. ¹H NMR (CDCl₃, 500 MHz)

7.72 (d, 8.9 Hz, 1H), 7.13 (dd, 2.4 & 8.8 Hz, 1H), 7.03 (d, 2.6 Hz, 1H),4.40 (s, 2H), 3.88 (s, 3H), 1.41 (s, 9H), 1.35 (s, 9H). LC-MS: 4.27 min.(m/Z=369.2, 263.2, 347.3).

EXAMPLE 34

N-Butyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofaran-3-yl]-N-methylacetamide

The title compound was prepared from1-tert-butyl-6-methoxy-3H-pyrano[3,4-b][1]benzofuran-3-one and butylmethyl amine using the procedure from Step C Example 15. LC-MS: 3.97min. (m/Z=360.4, 382.3, 276.2, 273.2).

EXAMPLE 35

2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-methyl-N-(3-methylbutyl)acetamide

The title compound was prepared from1-tert-butyl-6-methoxy-3H-pyrano[3,4-b][1]benzofuran-3-one and i-amylmethyl amine using the procedure from Step C Example 15. LC-MS: 4.11min. (m/Z=374.4, 396.3, 290.3, 273.2).

EXAMPLES 36˜49

Step A. 1-(5-Fluoro-2-mercaptophenyl)ethanone

The title compound was prepared from commercially available5-fluoro-2-mercaptobenzoic acid using the method of Topolski (J. Org.Chem. 1995, 60, 5585). It was purified using SGC with 15˜25% EtOAc inhexanes. ¹H NMR (CDCl₃, 500 MHz)

7.58 (dd, J_(H-H)=2.8 Hz, J_(H-F)=9.2 Hz, 1H), 7.31 (dd, J_(H-H)=8.7 Hz,J_(H-F)=5.3 Hz, 1H), 7.12 (ddd, J_(H-H)=8.7 & 2.8 Hz, J_(H-F)=7.6 Hz,1H), 4.49 (s, 1 SH), 2.64 (s, 3H).

Step B. 1-(5-Fluoro-3-methyl-1-benzothien-2-yl)-2,2-dimethylpropan-1-one

To a solution of 5.20 g 1-(5-fluoro-2-mercaptophenyl)ethanone in 100 mLanhydrous DMF was added 5.47 g 1-bromopinacolone and 10.95 g cesiumcarbonate. The resulting mixture was stirred at room temperatureovernight and then heated at 70° C. for 3 days. After diluting thereaction mixture with ice and water, it was extracted with ether severaltimes. The combined ether extract was washed with 0.05 N NaOH (2×),water (3×), and saturated brine, dried over anhydrous Na₂SO₄, andevaporated to give the crude product. The latter was purified by SGCusing 10˜15% EtOAc in hexanes to give the title compound as an oil. ¹HNMR (CDCl₃, 500 MHz)

7.77 (dd, J_(H-H)=8.7 Hz, J_(H-F)=4.8 Hz, 1H), 7.49 (dd, J_(H-H)=2.5 Hz,J_(H-F)=9.6 Hz, 1H), 7.24 (ddd, J_(H-H)=2.5 & 8.7 Hz, J_(H-F)=8.7 Hz,1H), 2.53 (s, 3H), 1.40 (s, 9H). LC-MS: 4.11 min. (m/Z=209.1, 251.1).

Step C. [2-(2,2-Dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]aceticacid

The title compound was prepared from1-(5-fluoro-3-methyl-1-benzothien-2-yl)-2,2-dimethylpropan-1-one usingthe procedure described in Step B Example 1. ¹H NMR (CDCl₃, 500 MHz)

7.82 (dd, J_(H-H)=8.8 Hz, J_(H-F)=4.7 Hz, 1H), 7.72 (dd, J_(H-H)=2.4 Hz,J_(H-F)=9.3 Hz, 1H), 7.32 (ddd, J_(H-H)=2.5 & 8.7 Hz, J_(H-F)=8.7 Hz,1H), 4.00 (s, 2H), 1.46 (s, 9H). LC-MS: 3.48 min. (m/Z=249.2, 277.2,317.2, 295).

Step D. Examples 36˜49

The title compounds were prepared from[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]acetic acid usingthe same procedure described in Step C Example 1 except the reaction wascarried out at 70° C. for 8˜20 hours.

TABLE 2 Examples 36~49

LC-MS Example R₁ R₂ t_(r), min. m/Z 36 n-Bu n-Bu 4.56 406.3, 428.2 37i-Bu i-Bu 4.53 406.3, 428 38 cyclopropylmethyl n-Pr 4.27 390.3, 412.2 39cyclohexyl Et 4.44 404.3, 426 40 n-Pr n-Pr 4.26 378.3, 400.2 41 n-Bu Et4.26 378.3, 400.2 42 i-Amyl Et 4.40 392.3, 414.2 43 n-Bu n-Pr 4.41392.3, 414.2 44 i-Amyl i-Amyl 4.78 434.3, 456.3 45

4.49 416.3, 438 46

4.46 416.3, 438 47

4.70 432.3, 454.2 48

4.77 432.1, 454.2 49 3,3-Dimethylbutyl Et 4.50 406.3, 428.2

EXAMPLES 50˜63

Step A. 1-(2-Mercaptophenyl)ethanone

The title compound was prepared from commercially available2-mercaptobenzoic acid using the method of Topolski (J. Org. Chem. 1995,60, 5585). It was purified using SGC with 15˜25% EtOAc in hexanes. ¹HNMR (CDCl₃, 500 MHz)

7.91 (d, 7.8 Hz, 1H), 7.33˜7.35 (m, 2H), 7.21˜7.25 (m, 1H), 4.51 (s,1H), 2.66 (s, 3H). LC-MS: 2.69 min. (m/Z=59.8, 135.0, 153.0).

Step B. 2,2-Dimethyl-1-(3-methyl-1-benzothien-2-yl)propan-1-one

The title compound was prepared from 1-(2-mercaptophenyl)ethanone and1-bromopinacolone using the procedure in Step B Examples 36˜49. ¹H NMR(CDCl₃, 500 MHz)

7.82˜7.88 (m, 2H), 7.44˜7.50 (m, 2H), 2.60 (s, 3H), 1.41 (s, 9H). LC-MS:4.06 min. (m/Z=233.4, 191).

Step C. [2-(2,2-Dimethylpropanoyl)-1-benzothien-3-yl]acetic acid

The title compound was prepared from2,2-dimethyl-1-(3-methyl-1-benzothien-2-yl)propan-1-one using theprocedure in Step B Example 1. ¹H NMR (CDCl₃, 500 MHz)

8.09 (d, 7.5 Hz, 1H), 7.88 (d, 7.1 Hz, 1H), 7.51˜7.58 (m, 2H), 4.06 (s,2H), 1.48 (s, 9H). LC-MS: 3.36 min. (m/Z=231.1, 259.1, 299.1, 277).

Step D. 1-tert-Butyl-3H-[1]benzothieno[2,3-c]pyran-3-one

The title compound was prepared from[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]acetic acid using theprocedure in Step D Examples 20˜32. ¹H NMR (CDCl₃, 500 MHz)

7.93 (d, 8.0 Hz, 1H), 7.62 (d, 8.0 Hz, 1H), 7.56˜7.59 (m, 1H), 7.38˜7.41(m, 1H), 6.70 (s, 1H), 1.52 (s, 9H). LC-MS: 3.61 min. (m/Z=259.2).

Step E. Examples 50˜63

Examples 50˜63 in Table 3 were prepared from1-tert-butyl-3H-[1]benzothieno[2,3-c]pyran-3-one and appropriate amineor amine HCl salt using a similar method as the one described in Step EExample 19.

TABLE 3 Examples 50~63

LC-MS Example R₁ R₂ t_(r), min. m/Z 50 n-Bu n-Bu 4.44 388.3, 410.3,304.2, 259.1 51 i-Bu i-Bu 4.41 388.3, 410.3, 304.2, 259.2 52cyclopropylmethyl n-Pr 4.15 372.3, 394.2, 288.2, 259.2 53 cyclohexyl Et4.32 386.3, 408, 259.2, 302.3 54 n-Pr n-Pr 4.13 360.3, 276.2, 382.3,259.2 55 n-Bu Et 4.14 360.3, 276.2, 382.3, 259.2 56 i-Amyl Et 4.66416.4, 438, 332.3, 259.2 57 n-Bu n-Pr 4.28 374.4, 290.3, 396.3, 259.2 58i-Amyl i-Amyl 4.30 374.4, 290.3, 396.3, 259.2 59

4.39 398.3, 420.3, 314.3, 259 60

4.35 398.3, 420.3, 314.3, 259 61

4.58 414.4, 436.3, 330.3, 259.2 62

4.61 414.4, 436.3, 330.3, 259.2 63 3,3-Dimethylbutyl Et 4.38 388.4,410.3, 304.2, 259.2

Functional Assays

Maxi-K Channel

The activity of the compounds can also be quantified by the followingassay.

The identification of inhibitors of the Maxi-K channel can beaccomplished using Aurora Biosciences technology, and is based on theability of expressed Maxi-K channels to set cellular resting potentialafter transient transfection of both α and β subunits of the channel inTsA-201 cells. In the absence of inhibitors, cells display ahyperpolarized membrane potential, negative inside, close to E_(K) (−80mV) which is a consequence of the activity of the Maxi-K channel.Blockade of the Maxi-K channel will cause cell depolarization. Changesin membrane potential can be determined with voltage-sensitivefluorescence resonance energy transfer (FRET) dye pairs that use twocomponents, a donor coumarin (CC₂DMPE) and an acceptor oxanol(DiSBAC₂(3)). Oxanol is a lipophilic anion and distributes across themembrane according to membrane potential. Under normal conditions, whenthe inside of the cell is negative with respect to the outside, oxanolis accumulated at, the outer leaflet of the membrane and excitation ofcoumarin will cause FRET to occur. Conditions that lead to membranedepolarization will cause the oxanol to redistribute to the inside ofthe cell, and, as a consequence, to a decrease in FRET. Thus, the ratiochange (donor/acceptor) increases after membrane depolarization.

Transient transfection of the Maxi-K channel in TsA-201 cells can becarried out as previously described (Hanner et al. (1998) J. Biol. Chem.273, 16289-16296) using FUGENE6™ as the transfection reagent. Twentyfour hours after transfection, cells are collected in Ca²⁺-Mg²⁺-freeDulbecco's phosphate-buffered saline (D-PBS), subjected tocentrifugation, plated onto 96-well poly-d-lysine coated plates at adensity of 60,000 cells/well, and incubated overnight. The cells arethen washed 1× with D-PBS, and loaded with 100 μl of 4 μM CC₂DMPE-0.02%pluronic-127 in D-PBS. Cells are incubated at room temperature for 30min in the dark. Afterwards, cells are washed 2× with D-PBS and loadedwith 100 μl of 6 μM DiSBAC₂(3) in (mM): 140 NaCl, 0.1 KCl, 2 CaCl₂, 1MgCl₂, 20 Hepes-NaOH, pH 7.4, 10 glucose. Test compounds are dilutedinto this solution, and added at the same time. Cells are incubated atroom temperature for 30 min in the dark.

Plates are loaded into a voltage/ion probe reader (VIPR) instrument, andthe fluorescence emission of both CC₂DMPE and DiSBAC₂(3) are recordedfor 10 sec. At this point, 100 μl of high-potassium solution (mM): 140KCl, 2 CaCl₂, 1 MgCl₂, 20 Hepes-KOH, pH 7.4, 10 glucose are added andthe fluorescence emission of both dyes recorded for an additional 10sec. The ratio CC₂DMPE/DiSBAC₂(3), before addition of high-potassiumsolution equals 1. In the absence of any inhibitor, the ratio afteraddition of high-potassium solution varies between 1.65-2.0. When theMaxi-K channel has been completely inhibited by either a known standardor test compound, this ratio remains at 1. It is possible, therefore, totitrate the activity of a Maxi-K channel inhibitor by monitoring theconcentration-dependent change in the fluorescence ratio.

The compounds of this invention were found to causeconcentration-dependent inhibition of the fluorescence ratio with IC₅₀'sin the range of about 1nM to about 20 μM, more preferably from about 10nM to about 500 nM.

B. Electrophysiological Assays of Compound Effects On High-conductanceCalcium-activated Potassium Channels

Human Non-pigmented Ciliary Epithelial Cells

The activity of high-conductance calcium-activated potassium (maxi-K)channels in human non-pigmented ciliary epithelial cells was determinedusing electrophysiological methods. Currents through maxi-K channelswere recorded in the inside-out configuration of the patch clamptechnique, where the pipette solution faces the extracellular side ofthe channel and the bath solution faces the intracellular side. Excisedpatches contained one to about fifty maxi-K channels. Maxi-K channelswere identified by their large single channel conductance (250-300 pS),and by sensitivity of channel gating to membrane potential andintracellular calcium concentration. Membrane currents were recordedusing standard electrophysiological techniques. Glass pipettes (Garner7052) were pulled in two stages with a Kopf puller (model 750), andelectrode resistance was 1-3 megohms when filled with saline. Membranecurrents were recorded with EPC9 (HEKA Instruments) or Axopatch 1D (AxonInstruments) amplifiers, and digital conversion was done with ITC-16interfaces (Instrutech Corp). Pipettes were filled with (mM); 150 KCl,10 Hepes, 1 MgCl₂, 0.01 CaCl₂, 3.65 KOH, pH 7.20. The bath(intracellular) solution was identical, except, in some cases, calciumwas removed, 1 mM EGTA was added and 20 mM KCl was replaced with 20 mMKF to eliminate calcium to test for calcium sensitivity of channelgating. Drugs were applied to the intracellular side of the channel bybath perfusion.

Human non-pigmented ciliary epithelial cells were grown in tissueculture as described (Martin-Vasallo, P., Ghosh, S., and Coca-Prados,M., 1989, J. Cell. Physiol. 141, 243-252), and plated onto glass coverslips prior to use. High resistance seals (>1 Gohm) were formed betweenthe pipette and cell surface, and inside out patches were excised.Maxi-K channels in the patch were identified by their gating properties;channel open probability increased in response to membranedepolarization and elevated intracellular calcium. In patches used forpharmacological analysis, removing intracellular calcium eliminatedvoltage-gated currents. Maxi-K currents were measured after depolarizingvoltage steps or ramps that caused channel opening.

The compounds of this invention were applied to the intracellular sideof the channel in appropriate concentrations (0.001 to 100 μM). Thecompounds reduced channel open probability, and this effect was reversedupon washout of compounds from the experimental chamber. The IC50 forblock of maxi-K channels under these conditions for the compounds ofthis invention ranged from about 0.5 nM to about 10 μM.

1. A compound of the structural formula I:

where or a pharmaceutically acceptable salt, enantiomer, diastereomer ormixture thereof: wherein, R represents hydrogen, or C₁₋₆ alkyl; Xrepresents —(CHR₇)_(p)—, or —(CHR₇)_(p)CO—; Y represents —CO(CH₂)_(n)—,(CH₂)_(n), —CH(OR)—, OR₆, or SR₆; Z═O or S; M1, M2, and M3 areindependently CH or N; Q represents, N; RY represents H, C₁₋₆ alkyl,—(CH₂)_(n)C₃₋₈ cycloalkyl, —(CH₂)_(n)C₃₋₁₀ heterocyclyl, —(CH₂)_(n)C₅₋₁₀heteroaryl, or —(CH₂)_(n)C₆₋₁₀ aryl; R_(w) represents H, C₁₋₆ alkyl,—C(O)C₁₋₆ alkyl, —C(O)OC₁₋₆ alkyl, —SO₂N(R)₂, —SO₂C₁₋₆ alkyl, —SO₂C₆₋₁₀aryl, NO₂, CN or —C(O)N(R)₂; R₂ represents hydrogen, C₁₋₁₀ alkyl, OH,C₂₋₆ alkenyl, C₁₋₆ alkylSR, —(CH₂)_(n)O(CH₂)_(m)OR,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₁₋₆ alkoxy,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₃₋₈cycloalkenyl,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₃₋₁₀ heterocyclyl, —N(R)₂, —COOR, or—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₆₋₁₀ aryl, said alkyl, cycloalkyl,heterocyclyl, or aryl optionally substituted with 1-5 groups selectedfrom R^(a); R₃ represents hydrogen, C-₁₋₁₀ alkyl, C₂₋₆ alkenyl,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₃₋₈ cycloalkyl,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)cycloalkenyl,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₃₋₁₀ heterocyclyl,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)COOR, —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₆₋₁₀aryl, —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)NHR₈,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)N(R)₂, —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)N(R)₃,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)N(R₈)₂,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)NHCOOR,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)N(R₈)CO₂R,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)N(R₈)COR,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)NHCOR,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)CONH(R₈), aryl,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₁₋₆ alkoxy, CF₃,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)SO₂R,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)SO₂N(R)₂,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)CON(R)₂,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)CONHC(R)₃,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)CONHC(R)₂CO₂R,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)COR₈, nitro, cyano or halogen, said alkyl,cycloalkyl, alkoxy, heterocyclyl, or aryl optionally substituted with1-5 groups of R^(a); R₄ and R₅ independently represent hydrogen, C₁₋₆alkoxy, OH, C₁₋₆ alkyl, C₁₋₆ alkyl-S, C₁₋₆ alkyl-CO—, C₁₋₆ alkenyl, C₃₋₈cycloalkoxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-S, C₃₋₈ cycloalkyl—CO—,COOR, SO₃H, —O(CH₂)_(n)N(R)₂, —O(CH₂)_(n)CO₂R, —OPO(OH)₂, CF₃, —N(R)₂,nitro, cyano, C₁₋₆ alkylamino, or halogen; R₆ represents hydrogen, C₁₋₁₀alkyl, —(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₆₋₁₀ aryl,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₅₋₁₀ heteroaryl, NR_(c)R_(d),—NR—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₆₋₁₀ aryl,—N—((CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₆₋₁₀ aryl)₂,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₃₋₁₀ heterocyclyl,—NR—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₃₋₁₀ heterocyclyl,—N—((CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₃₋₁₀ heterocyclyl)₂ (C₆₋₁₀ aryl)O—,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)C₃₋₈ cycloalkyl, —COOR, —C(O)CO₂R, saidaryl, cycloalkyl, heteroaryl, heterocyclyl and alkyl optionallysubstituted with 1-3 groups selected from R^(a); R_(c) and R_(d)independently represent H, C₁₋₆ alkyl, C₂₋₆ alkenyl, —(CH₂)_(n)C₆₋₁₀aryl, —(CH₂)_(n)C₅₋₁₀ heteroaryl, C₁₋₆ alkylSR, —(CH₂)_(n)O(CH₂)_(m)OR,—(CH₂)_(n)C₁₋₆ alkoxy, or —(CH₂)_(n)C₃₋₈ cycloalkyl; or R_(c) and R_(d)taken together with the intervening N atom form a 4-10 memberedheterocyclic carbon ring optionally interrupted by 1-2 atoms of O, S,C(O) or NR, and optionally having 1-4 double bonds, and optionallysubstituted by 1-3 groups selected from R^(a); R₇ represents hydrogen,C₁₋₆ alkyl, —(CH₂)_(n)COOR or —(CH₂)_(n)N(R)₂, R₈ represents—(CH₂)_(n)C₃₋₈ cycloalkyl, —(CH₂)_(n) 3-10 heterocyclyl, C₁₋₆ alkoxy or—(CH₂)_(n)C₅₋₁₀ heteroaryl, —(CH₂)_(n)C₆₋₁₀ aryl said cycloalkyl,heterocyclyl, aryl or heteroaryl optionally substituted with 1-3 groupsselected from R^(a); R^(a) represents F, Cl, Br, I, CF₃, N(R)₂, NO₂, CN,—COR₈, —CONHR₈, —CON(R₈)₂, —O(CH₂)_(n)COOR, —NH(CH₂)_(n)OR, —COOR,—OCF₃, —NHCOR, —SO₂R, —SO₂NR₂, —SR, (C₁-C₆ alkyl)O—,—(CH₂)_(n)O(CH₂)_(m)OR, —(CH₂)_(n)C₁₋₆ alkoxy, (aryl)O—, —OH, (C₁-C₆alkyl)S(O)_(m)—, H₂N—C(NH)—, (C₁-C₆ alkyl)C(O)—, (C₁-C₆ alkyl)OC(O)NH—,—(C₁-C₆ alkyl)NR_(w)(CH₂)_(n)C₃₋₁₀ heterocyclyl-R_(w), —(C₁-C₆alkyl)O(CH₂)_(n)C₃₋₁₀ heterocyclyl-R_(w), —(C₁-C₆ alkyl)S(CH₂)_(n)C₃₋₁₀heterocyclyl-R_(w), —(C₁-C₆ alkyl)-C₃₋₁₀ heterocyclyl-R_(w),—(CH₂)_(n)-Z¹—C(═Z²)N(R)₂, —(C₂₋₆ alkenyl)NR_(w)(CH₂)_(n)C₃₋₁₀heterocyclyl-R_(w), —(C₂₋₆ alkenyl)O(CH₂)_(n)C₃₋₁₀ heterocyclyl-R_(w),—C₂₋₆ alkenyl)S(CH₂)_(n)C₃₋₁₀ heterocyclyl-R_(w), —(C₂₋₆ alkenyl)-C₃₋₁₀heterocyclyl-R_(w), —(C₂₋₆ alkenyl)-Z¹—C(═Z²)N(R)₂, —(CH₂)_(n)SO₂R,—(CH₂)_(n)SO₃H, —(CH₂)_(n)PO(OR)₂, —(CH₂)_(n)OH,—(CH₂)_(n)(CHR₇)_(q)(CH₂)_(m)OPO(OR)₂, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl,C₃₋₁₀ heterocyclyl, C₂₋₆ alkenyl, and C₁-C₁₀ alkyl, said alkyl, alkenyl,alkoxy, heterocyclyl and aryl optionally substituted with 1-3 groupsselected from C₁-C₆ alkyl, CN, NO₂, —(CH₂)_(n)OH, —(CH₂)_(n)OPO(OR)₂,CON(R)₂ and COOR; Z¹ and Z² independently represents NR_(w), O, CH₂, orS; m is 0-3; n is 0-3; p is 0-3 and q is 0-1.
 2. A compound according toclaim 1 wherein Q is —N— and Y is —CO(CH₂)_(n).
 3. A compound accordingto claim 2 wherein n=0, Z is S, and R₆ is C₁₋₆ alkyl, (CH₂)_(n)C₆₋₁₀aryl, (CH₂)_(n)C₅₋₁₀ heteroaryl, (CH₂)_(n)C₃₋₁₀ heterocyclyl,NR_(c)R_(d) or (CH₂)_(n)C₃₋₈ cycloalkyl, said alkyl, aryl, heteroaryl,heterocyclyl and alkyl optionally substituted with 1 to 3 groups ofR^(a).
 4. A compound according to claim 3 wherein M1, M2 and M3 are CH,X is —(CHR₇)_(p)CO—, p is 1-3, R₂ is C₁₋₁₀ alkyl or C₁₋₆ alkylOH and R₃is (CH₂)_(n)C₃₋₁₀ heterocyclyl, said heterocyclyl and alkyl optionallysubstituted with 1 to 3 groups of R^(a).
 5. A compound according toclaim 2 wherein n=0, Z is O, and R₆ is C₁₋₆ alkyl, (CH₂)_(n)C₆₋₁₀ aryl,(CH₂)_(n)C₅₋₁₀ heteroaryl, (CH₂)_(n)C₃₋₁₀ heterocyclyl, NR_(c)R_(d) or(CH₂)_(n)C₃₋₈ cycloalkyl, said alkyl, aryl, heteroaryl, heterocyclyl andalkyl optionally substituted with 1 to 3 groups of R^(a).
 6. A compoundaccording to claim 5 wherein M1, M2 and M3 are CH, X is —(CHR₇)_(p)CO—,p is 1-3, R₂ is C₁₋₁₀ alkyl or C₁₋₆ alkylOH and R₃ is (CH₂)_(n)C₃₋₁₀heterocyclyl, said heterocyclyl and alkyl optionally substituted with 1to 3 groups of R^(a).
 7. A compound according to claim 1 where a freehydroxyl group is present, said hydroxyl group optionally derivatized togive a phosphate group represented as —OPO(OH)₂.
 8. A compound which is:N,N-Bibutyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetamide,2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N,N-diisobutylacetamide,2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N,N-dipropylacetamide,N-Butyl-2-[2-(2,2-ethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethylacetamide,2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofaran-3-yl]-N,N-bis(3-methylbutyl)acetamide,2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethyl-N-(3-methylbutyl)acetamide,N-Butyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-propylacetamide,N-(3,3-Dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetamide,N-(3,3-Dimethylbutyl)-2-[2-(2,2-ethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethylacetamide,2-(2-Benzoyl-5-methoxy-1-benzofuran-3-yl)-N,N-dibutylacetamide,2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N,N-di-n-butylacetamide;2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N,N-diisobutylacetamide;2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N,N-dipropylacetamide;N-butyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N-ethylacetamide;2-[2-(2,2-methylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N-ethyl-N-(3-methylbutyl)acetamide;N-butyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N-propylacetamide;2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N,N-bis(3-methylbutyl)acetamide;N-(3,3-dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzothien-3-yl]-N-ethylacetamide;N-Butyl-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-methylacetamide;2-[2-(2,2-Dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-methyl-N-(3-methylbutyl)acetamide;2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N,N-di-n-butylacetamide;2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N,N-diisobutylacetamide;2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N,N-dipropylacetamide;N-butyl-2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N-ethylacetamide;2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N-ethyl-N-(3-methylbutyl)acetamide;N-butyl-2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N-propylacetamide;2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N,N-bis(3-methylbutyl)acetamide;N-(3,3-dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-5-fluoro-1-benzothien-3-yl]-N-ethylacetamide;2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N,N-di-n-butylacetamide;2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N,N-diisobutylacetamide;2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N,N-dipropylacetamide;N-butyl-2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N-ethylacetamide;2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N-ethyl-N-(3-methylbutyl)acetamide;N-butyl-2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N-propylacetamide;2-[2-(2,2-dimethylpropanoyl)-1-benzothien-3-yl]-N,N-bis(3-methylbutyl)acetamide;N-(3,3-dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl-1-benzothien-3-yl]-N-ethylacetamide;or a pharmaceutically acceptable salt, enantiomer, diastereomer ormixture thereof.
 9. A method for the treatment ocular hypertension orglaucoma comprising administering to a patient in need thereof atherapeutically effective amount of a compound of structural formula I.10. A composition comprising a compound of formula I of claim 1 and apharmaceutically acceptable carrier.
 11. The composition according toclaim 10 wherein the compound of formula I is applied as a topicalformulation, said topical formulation administered as a solution orsuspension and optionally contains xanthan gum or gellan gum.
 12. Acomposition according to claim 11 wherein one or more of an activeingredient belonging to the group consisting of: β-adrenergic blockingagent, parasympatho-mimetic agent, sympathomimetic agent, carbonicanhydrase inhibitor, EP4 agonist, a prostaglandin or derivative thereof,hypotensive lipid, neuroprotectant, and/or 5-HT2 receptor agonist isoptionally added.
 13. A composition according to claim 12 wherein theβ-adrenergic blocking agent is timolol, betaxolol, levobetaxolol,carteolol, or levobunolol; the parasympathomimetic agent is pilocarpine;the sympathomimetic agent is epinephrine, brimonidine, iopidine,clonidine, or para-aminoclonidine, the carbonic anhydrase inhibitor isdorzolamide, acetazolamide, metazolamide or brinzolamide; theprostaglandin is latanoprost, travaprost, unoprostone, rescula, orS1033, the hypotensive lipid is lumigan, the neuroprotectant iseliprodil, R-eliprodil or memantine; and the 5-HT2 receptor agonist is1-(2-aminopropyl)-3-methyl-1H-imdazol-6-ol fumarate or2-(3-chloro-6-methoxy-indazol-1-yl)-1-methyl-ethylamine.